Jay Feldman 0:12
Welcome to Episode 67 of the energy balance podcast, where we teach you how to live without constant hunger and cravings, fatigue, brain fog, poor sleep and other low energy symptoms by maximizing your cellular energy. I'm Jay Feldman. I'm a health coach and independent health researcher, and joining me again today is my good friend Mike Fave. Mike and I have been studying health and nutrition together for a long time now, and Mike also draws on his experiences from working within the healthcare industry. Today's episode is part five of our series discussing non alcoholic fatty liver disease. And in today's episode, we'll be focusing on endotoxin and PUFA as primary causes of fatty liver disease. And throughout the series, we've been discussing the general mechanisms and physiology underlying this condition, and we've been spending a lot of time on this, because this is a pathology that directly applies to virtually every other chronic health issue or symptom out there. And we have been working to try to simplify these mechanisms by referring to some graphics. So if you'd like to see those, then you might want to watch this episode on YouTube, but we'll also make sure to describe these graphics verbally. And throughout the series, we have been diving pretty deep into the physiology, but toward the end, we'll discuss what this all means as far as diet and lifestyle and supplements for reversing this situation and virtually every other health issue that's related to the same pathology. But if digging into the physiology is not as much of your cup of tea, if that doesn't interest you as much, or if you're new to this podcast, then I'd recommend you go back and check out episodes one through seven, where we took some time to build a foundation as far as the bioenergetic view of health is concerned. And in today's episode in particular, we'll be discussing how endotoxin drives inflammation and stress while down regulating our metabolism. We'll be talking about why alcoholic fatty liver disease is not all that different from non alcoholic fatty liver disease. We'll be talking about the protective effects of saturated fats and non alcoholic fatty liver disease. We'll be talking about how endotoxin and polyunsaturated fats can cause non alcoholic fatty liver disease, and we'll also be discussing nutrient deficiencies that contribute to energy failure and non alcoholic fatty liver disease. To check out these show notes for today's episode, you can head over to Jay Feldman wellness.com/podcast you can take a look at the studies and articles and anything else that we discuss throughout today's episode, and if you are dealing with any of the chronic health issues or symptoms that we've been discussing throughout the series, maybe that is fatty liver or insulin resistance or other related conditions like diabetes and heart disease, or maybe that's other low energy symptoms like chronic cravings and hunger, fatigue or joint pain or weight gain, or digestive symptoms like bloating or inflammation, brain fog, poor sleep, hormonal imbalances, or any other low energy symptoms or chronic health issues like autoimmune conditions, and if you are experiencing any of those things, then I'd highly recommend you head over to Jay Feldman wellness.com/energy, where you can sign up for a free energy balance mini course, where I'll explain how these different symptoms and conditions are really caused by a lack of energy. And I'll also walk you through the main things that you can do from a diet and lifestyle perspective, to maximize your cellular energy and resolve these symptoms and conditions. So to sign up for that free energy balance mini course, head over to Jay Feldman wellness.com/energy, and with that, let's get started. All right. So up until now, we've talked about the underlying mechanisms that are going on in non alcoholic fatty liver disease, and even alcoholic fatty liver disease that involve these issues, with mitochondrial respiration, with energy production, we end up with a lack of energy and all these other problems, and that causes fat accumulation as a backup response. And we talked about how some of the evidence for this, beyond just seeing those mechanisms, is also that we see elevated stress hormones, and that you can cause the same situation by just using elevated stress hormones. And so you see particular hormonal changes along the way, and all those things reflect what's going on in this state, in this condition. Now, what we haven't talked about yet and have been kind of tiptoeing around, is what actually causes this situation, what causes the elevated stress hormones, what causes the inhibited energy production and elevated reactive oxygen species and oxidative stress and all of the problems that come with that, including the fat production. Again, just to clarify too, we're still on the fat production side. Of what's going on in fatty liver, what is leading to the production of fat. We still have not talked about the clearance of fat as much. We've talked about it a little bit because it's involved, but there are some specifics that we'll talk about there later on. But so as far as what some of the main causes are of this situation, of this protective, adaptive response to increase fat production in the liver. We have alluded to, or at least mentioned endotoxin a little bit, because it really is one of those, one of the main factors, and there's a ton to dig into when it comes to endotoxin, and potentially other gut toxic toxins as well, in their relationship with with fatty liver. So let's, uh, let's start there, just to give a brief overview for someone who's not aware of endotoxin, and maybe hasn't been listening to us all that much, and because it's something we talk about a lot, but maybe if they're not aware, endotoxin is a component of bacterial cell walls. Uh, generally, we're talking about the bacteria that are living in our guts, and we want that endotoxin to stay there. When it does not stay there and ends up in our bloodstream and throughout our bodily systems, we tend to see a lot of issues. We talked about it in terms of various other metabolic issues in the past. Talked about in terms of heart disease and high blood pressure and virtually every other issue that exists, health wise and fatty liver is certainly no, no exception there endotoxin instead, seems to have a very direct causative role here and again, when we're talking about this, what this really comes back to is what's going on With the bacterial population in our guts, and just our gut health overall. So, yeah, let's start with that. You want to kick us off Mike?

Mike 6:49
yeah. So the first thing that and I you prefaced it, you prefaced it perfectly, is the first thing is the endotoxin comes directly from bacteria in our gut. It can come from any bacteria, in general, but the endotoxin that we're seeing in most of these chronic states that involve metabolic syndrome, heart disease, diabetes, chronic kidney disease, fatty liver disease, any impaired glucose tolerance, obesity, is primarily coming from the gut, the other and it's, And it's, it's, it's a chronic low level drip coming from the gut. It's not some massive infection to a large extent. It's, you know, like, if you were to have, like, a huge skin infection or a boil or cellulitis or something like that, it or if you had pneumonia, it's more specific to just a trickle of endotoxin coming in from the grub from the gut, usually from an overgrowth of gram negative bacteria. And this is gram negative are the main bacteria that produce endotoxin gram positive. And this is the difference between gram negative and gram positive. Is the structure of the cell wall which endotoxin lipopolysaturide is a component of. So the gram negative basically can produce lipopolysaturide, whereas the gram positive don't really produce as much lipopolysaturide, if they produce any at all, but they do produce other compounds, I think that's called lipo to COIC acid is what Staph aureus can produce, and it's has similar immune stimulating effects as lipopos polysaturide or endotoxin. So anytime we're talking about bacterial products from the intestine or or endotoxin in general, they're kind of grouped together individually. They can all have different effects, but when it boils down to it, at the end of it, many of these pathogenic bacterial products can cause immune stimulation and a host of metabolic issues in the body through stimulating that inflammatory response. So in fatty liver, there's no difference here. Fatty Liver, basically you can see having in fatty liver cirrhosis and Nash. Sorry, I guess to go fatty liver, Nash and cirrhosis, the amounts of endotoxin are actually increasing over time, and the damage to the liver is increasing over time, and basically the adaptive processes of the body are degrading so and you can basically, what you see in all these states is higher circulating levels of endotoxin. And we have a graph, I don't know if you want to pull it up, and we can talk about it a little bit.

Jay Feldman 9:20
Before we do that, real quick, I just wanted to because you made an important point about the the small trickle of endotoxin, as opposed to this being an obvious infection, and so that's sometimes called low grade endotoxemia. It's something you see in various chronic health conditions and metabolic issues, and it's becoming more well recognized, but it is, as you said, this this would have in a major infection, you would see very high amounts of these things, but low amounts over time are still a huge, huge problem driving constant chronic inflammation and chronic impaired energy production. So it was an important distinction to make. And then just I wanted to, I'll pull up the graph now and then when we do it, maybe we can also just clarify the difference between. Yeah, fatty liver, which is NAFLD, Nash and cirrhosis.

Mike 10:06
Okay, so basically, what you can see on the top left is the actual endotoxin scale. So what they're looking at here is they're looking at control versus non alcoholic, fatty liver disease versus non alcoholic. Steal hepatitis. That's Nash. Yeah, that's Nash. So to clarify, non alcoholic, fatty liver disease, and we've talked about this in previous episodes, is just the buildup of fat inside the liver, non alcoholic, and it's usually it doesn't come with a severe pathology to the liver. It's more just like the liver storing in excess of fat. There is pathology there, but it's not to the extent that is extremely damaging. Whereas non alcoholic steal hepatitis is where you actually have, like, severe inflammation of the liver going on with the buildup of fat. So NAFLD can progress to n to Nash, but it doesn't always do. So most of the times it doesn't. And then the next step after Nash is cirrhosis, and that you can see that on the bottom, what they're looking at here is you can you can look at what's going on, as far as how much endotoxin you have going into the blood, what you have in your serum, and that's what they're looking at. But there's also other markers to look at, so there's SCD 14, there's and then there's what they have on the bottom is tumor necrosis factor alpha receptor two. So they're looking at the different receptors for the cytokine tumor necrosis factor alpha, and then SCD 14 is a protein that gets released during inflammation, particularly with endotoxemia, and it can help scavenge some of the endotoxin molecules and whatnot, so the they're up regulating as a protective function. Same thing with tumor necrosis factor alpha. This cytokine releases lipids, or stimulates the liver to create and then release lipids into the blood to bind up the endotoxin in the blood and help to eliminate that immune response. So the what they're trying the reason researchers in most of the endotoxin studies will look at all these factors, because they say, Okay, we have endotoxin, but is it causing an effect? Because, and the reason this is important because in certain studies, like the the saturated fat studies, where they feed saturated fat to people and they show increases in serum endotoxin, they don't often have increases in these inflammatory markers like SCD 14 or tumor necrosis factor alpha to any large extent, maybe minor. And so basically, what that's saying is, in those saturated fat feeding studies, the endotoxin that's getting into the blood isn't particularly active, as far as stimulating an immune response. And this goes hand in hand with the overall pathology of fatty liver and the overall function of TU necrosis factor alpha and what endotoxin triggers. So the endotoxin, once it gets into the bloodstream, once it gets into the serum, it will trigger the depending on what cells it interacts with, if it gets a hold, if it interacts with like macrophages, then the macrophages, which are immune cells, will release tumor process factor alpha, the tumor necrosis factor alpha, will stimulate the liver to produce lipids. That's your LDL. That's your triglycerides. That's you have the chylomicrons coming in from the gut, which is basically all a fat bound up into certain, certain structure with like fat globules that they can be processed. They move through the lymph, all that type of stuff, and essentially those fatty substances can bind endotoxin. Now, why can they buy and bind endotoxin? Endotoxin has a lipid tail, and the lipid tail can interact with these fatty acids. And basically, once it's bound into there, it doesn't stimulate that immune response. So the body is increasing fatty acid production at the liver and in the blood to protect against that endotoxin, to basically bind it up and not stimulate, not stimulate, the the macrophages and and the the other immune cells in the body to have such an inflammatory response. So it's a protective mechanism. Cholesterol production and fat production by the liver elevates in many chronic states and many different states of inflammation. So overall, there's a reason that that's going on. Now the the what I want to get to really quick is, why does, why is endotoxin so toxic to the body? Why is the immune system have such a strong response to it? Well, basically what they look at in cell culture studies, because this is, this is how you're going to be able to see what's going on. There's a couple mechanisms by which this occurs. Endotoxin can directly damage the mitochondria and cause like malformation in the mitochondria, so it which is impairing cellular energy production directly. And we see that in non alcoholic fatty liver disease. And then when the immune system gets a hold of endotoxin, it's basically saying we have an. Infection going on, it like triggers that response, and it triggers a whole bunch of a whole bunch of mechanisms to deal with this endotoxin. And one some of those things include production of cytokines that stimulate inflammation, and then also in increased productions in nitric oxide and through inducible nitric oxide, or nitric oxide synthase. And what this does this nitric oxide, then again, directly impairs mitochondrial function and the the the immune system is up regulating with endotoxin, specifically because when you when the immune system finds these different components of the bacteria or the or the fungus or the parasite or the virus inside the body. It basically signaling the body, hey, we have some stuff here that you know doesn't necessarily belong. Maybe there's something else going on and the it's it also depends on the state. So endotoxin will in an unhealthy person, somebody who's been eating large amounts of polyunsaturated fats, been kind of eating a crap diet for a long period of time, has significant amount of stress. The response will be stronger from the endotoxin, because the immune system will be primed towards this. This response, especially if somebody's loaded up on omega six fatty acids, which stream stimulates strong, inflammatory production of, or stimulate the production of strong, infla inflammatory prostaglandins. So, and basically that's what you see in in some of the studies with alcohol feeding to induce liver damage with endotoxin, when they give corn oil, makes the effect like, which is high in Omega six, like, strongly, strongly increases the effect. So, but if you So, basically, your your state of your body will affect will determine the effect from endotoxin. If you have less polyunsaturated fatty acids and incorporated into your tissues and less available for strong inflammatory media response, you may not get us as as strong an effect. And you see this bit in the studies as well, where, when they replace the diet with monounsaturated saturated fatty acids, there, they can lower some of the inflammatory mediators, and they also can lower some of the damage to the cells, because the cells aren't loaded up on polyunsaturated fatty acid. And this will tie into that. Jay is actually going to cover this in in a like once we get through the endotoxin, deoxidative stress side of endotoxemia. So the next the some interesting studies have been shown with endotoxin, as far as fatty liver goes, go ahead.

Jay Feldman 17:35
yeah. I just wanted to summarize a bit so you had mentioned that the main reason why endotoxin is a problem is because it inhibits mitochondrial respiration. Talked about that. So that's part one most important thing that we've that we're kind of getting at, is that it that is one of the main mechanisms through which it's causing the issue that is fat production. So that's one area that it does it, but also because it does that, it triggers inflammation. You mentioned TNF alpha as one of the markers of that, and that's what that study with the grass was looking at. So I'll come back to that in a second. So we have inhibited respiration, and the fact that endotoxin is known as an issue, our bodies know it's an issue. So then it triggers inflammation to deal with that problem, and then, and so we see the markers of that, and it also triggers some other things to deal with, to deal with endotoxin. I guess I shouldn't say inflammation directly. It's triggering, triggering inflammatory markers, because it's causing inflammation, but it's also triggering processes that help to deal with endotoxin. So these are things that a will produce fats, which help to protect against it and bind with endotoxin. As you mentioned, and then help us excrete it, and some other enzymes and things that help to.

Mike 18:47
Yeah, alkaline phosphatase is an enzyme, and it will induce that will degrade endotoxin. So yeah, it the body up regulates a series of defenses to deal with it.

Jay Feldman 18:57
Right, right and so those are all things that we're seeing in fatty liver. And then as this problem of the endotoxin continues like longer and longer, and initially, you know you're dealing with that issue acutely, but it continues on and on, we see more and more inflammation and less and less of a capacity or an ability to deal with that endotoxin response. Yeah, so that's, that's what we're seeing in that graph. So just to pull that up real quick, and then we'll go and then we'll go on to those other studies and things, just to contextualize the graph, initially what we're seeing in non alcoholic fatty liver disease, which is the less severe version, right? That's that initial defensive response. Initially what we're seeing, well, the first thing is that we know that we're seeing elevated endotoxin levels, right? That was that first graph that showed elevated endotoxins, toxin levels in non alcoholic, fatty liver disease. And the step beyond that, which is Nash, where it's actually becoming inflamed, the steatosis, steel, hepatitis. Steel hepatitis, right? Yeah, which is the liver inflammation. So we're seeing the increase in endotoxin levels as the disease progresses. We're also seeing in. Increases in these defensive responses, right? So those SCD 14, yep, we're also seeing but then what's interesting, and we had mentioned, this is the change in inflammation, so we're using this TNF receptor as a marker there, and initially a non alcoholic fatty liver disease, you actually see a decrease, and that's because it is, and it's not as in this case, it wasn't statistically significant, but close, you know, you're seeing at least a relative decrease. Or if you want to say it's the same, that's fine as a control, where, because the body is adequately defending the endotoxin, it's responding properly and there's no continued inflammation, but when it continues on to the point where it's becoming Nash you see an increase in the in the inflammation side of things.

Mike 20:45
Well basically what's going on with the the drop and tumor necrosis factor alpha receptor levels is that once you have that initial stimulus for it, the fatty acids will bind that that endotoxin. And that's what you're seeing with NAFLD. The fatty acids in the serum in the liver are binding up that endotoxin, and then there's less endotoxin able to stimulate the production of tumor necrosis factor alpha, right? So it's that's the protective mechanism going on there. That's what you would like to see happen. Ideally, you'd want to resolve the endotoxemia. But yeah. So go ahead. Sorry, I just wanted to...

Jay Feldman 21:24
Well, and that fats, producing the fats to help reduce the endotoxin, will definitely help with the endotoxemia, assuming that there's not this constant, continuous flow of endotoxin, which, as you're saying, that's really where that then that's the progression, yeah, in this scenario, yeah. And so then they show on a separate graph. This is when you're looking at D versus C. They're looking at the same measure, but they're looking at Nash versus cirrhosis, which Cirrhosis is that level beyond Nash, and they're looking at the TNF receptor, TNF alpha receptors. And this, the reason why they're doing it this way is because if you saw cirrhosis on the last graph, it would it would be way above the range that they're using. If we look, here's the 3.5 and on this graph, it's right here. So that bar would be like, way up here, somewhere, somewhere around there would be off the graph, basically, to show what's going on in cirrhosis, where you're seeing such an increase in inflammation. So we're seeing just a, I wouldn't say collapse of the defensive response, but that the defensive response has been unsuccessful, right? It's continued to try, and you're going into deeper layers, but it's continued to be unsuccessful, and that's leading to this degenerative state.

Mike 22:33
Well, you have legitimate damage to the protective functions, right? Like your liver at this point, which is coordinating this response, has had so much apoptosis of the actual hepatocytes that they're being replaced with fibrotic tissue from the fibroblasts. So they're not there's no there's no functional hepatocytes there. The liver is just like it's been completely decimated by this continued endotoxin response. And then you see, like the tumor necrosis factor alpha receptor levels are going to be higher because there's going to be, like, a continuous response, because you're not able to mount that protective response anymore.

Jay Feldman 23:09
Or at least it hasn't been effective so far. So it's a continued deepening, there a continued depth of response. So that that's, I think, a really helpful set of graphs to see the role of endotoxin and how the responses play out. But as you were going to get to there are other studies too that are just looking at the role of endotoxin in non alcoholic fatty liver disease and its progression that are also very elucidating into how much of a problem it actually is. And we'll talk about the PUFA studies in a bit and alcohol as well. But leaving those aside. I know there are some other things to it you were going to get at.

Mike 23:43
So I just wanted to, we're going to go, we'll go, I want to go over those studies. But I just wanted to give the like, the actual like timeline for how, how things kind of develop with endotoxin, because I feel like the initial piece I gave, there's so many interrelated parts moving all over. I think it's easier to put it in like a, I guess, a linear flow, so you have endotoxin. It comes in through the gut. It when it gets into the gut, the if an immune cell gets a hold of it, the immune cells gonna say, Hey, we got a problem going on here. It's going to release a whole bunch of alarm, alarming signals. Those are your cytokines, probably a decent amount of inflammatory cytokines, including tumor necrosis bacteria, alpha when, when that's released, it's going to trigger the liver to increase fat production and to increase the exportations of fat from the liver. So it's going to be LDL, triglycerides. The other thing that happens is, in this process, the inflammatory cytokines that are released by the immune cells, which include its tumor causes, factor alpha, but also interleukin six, that'll trigger the the down regulation of your steroid hormone per. Reduction primarily your steroids. It'll lower the thyroid pathway and it will increase glucocorticoid signaling from the adrenal glands. So it's increasing the liver production of fats, and then it's increasing glucocorticoid signaling as well, while lowering thyroid and lowering the steroids that, for example, testosterone, progesterone. So overall, it's like creating a huge shift, and it does that not only at the adrenal glands, not only at the testicles or the ovaries. It's doing that at the hypothalamic and pituitary level as well, and then also the thyroid. So it's like a like the tendotoxin is like a huge shift, and also endotoxin will trigger increased production of serotonin from the gut. So it's, it's like this primary mediator that's deranges All of these systems, and then at the cellular level, the endotoxin is actually will can derange the mitochondria itself. And then some of the mediators that are produced by the immune cells can have a negative impact on mitochondrial function, and one of those, just as an example, being nitric oxide. So endotoxin is a huge problem in in the body in general, and the body has a whole host of systems to detoxify endotoxin. So while it has that fatty acid process as well in the gut, bile acids degrade endotoxin, alkaline phosphatase is an enzyme that can degrade endotoxin, and before endotoxin actually even gets into the bloodstream, it has to move through the lymphatic system, because it's unless the gut barrier is actually completely destroyed. It has to move through the lacteals, because it gets absorbed with the fat that are an extension of the lymphatic system that pulls the fat that you digest into the lymphatic system, moves it through part of the lymphatic system. So it's getting exposed to a whole host of immune cells, because the lymphatic system is extremely rich in immune cells, and then it gets into the serum, and it has to get past all of the lipoproteins and everything else. So when you're seeing somebody with these marginally higher levels or low levels of endotoxin, they could there that endotoxin that you're seeing in the serum is actually going through a whole host of other processes before you're even seeing that endotoxin in the serum. And it the endotoxin itself has changes, all of these, these processes that I just mentioned previously. So it's endotoxin is one of the primary poisons I think, that we see with most, if not all of these diseases. And it's it's ubiquitous because it comes from gut bacteria. And this is why, I think, when you see somebody who has any type of gut issue, pretty much everything goes awry. The whole system gets deranged, because you have these microbial products coming in from the intestine and kind of just deranging the whole system hormonally, then, and at the hormonal level, at the at the neurotransmitter level, what's going on with the liver, what's going on with the gut? So it's, it's, it's such a primary, central toxin in the system. And I think this is why Pete It's something that Pete has harped on a lot in his articles, as being, as being something to really focus on, make sure that there's nothing irritating in the gut. There's no endotoxin in production in the gut. So that's like a general idea of what goes on with endotoxin as far as more specific in the fatty liver. And now, unless you want to add anything I can get into these other studies that we talked about.

Jay Feldman 28:31
No, I don't think so. I think those that was all good, just to clarify too. So the you'd mentioned, unless the gut barrier is having a problem, the endotoxin will have to go through the, eventually, through the lymphatic system, in order to get absorbed. And that requires, as you mentioned, it, it's fat mediated, right? The specifically saturated fats are binding with it, and the it's, they use these, um, these lipid rafts, right, right? It's, it's like a conglomeration called a lipid raft. And so some people will point to that as being a bad thing, but it's actually really the safest way to get rid of endotoxin, because it, as you mentioned, goes through all of these kind of barriers to protect it and detoxify it, then it goes to the liver, where it can be further detoxified. That's the reason why that can be better is because a if you leave endotoxin in the gut, it will, on its own, damage the intestinal barrier and cause intestinal permeability and then come straight into the bloodstream. So if you have endotoxin in the gut, it is much better to have it be transported with the saturated fats. This is not a reason to avoid saturated fats, as some people in the bioenergetic community would suggest. I mean, at least that's not our view. So so I just wanted to clarify that, and then also, real quick, that intestinal permeability, either caused by endotoxin or anything else, will bypass all of that and then cause your bloodstream. Yep, exactly. And so we'll talk about some things that'll cause that and are worth considering as mediators, again, between this endotoxin and fatty liver.

Mike 29:59
So the one thing I do want to point out those, if there is intestine and we're going to talk about it, but if there is intestinal permeability where endotoxin is leaking through, it doesn't go directly into regular circulation. Has to go to the liver first, because it goes through the portal vein. So the liver is like, liver is like, the number one target for endotoxin pretty much all the time. That's why you've seen in high endotoxin states, the liver takes like a huge hit. It gets, it gets pretty much beat up by endotoxin, because the endotoxin is such a poison to energetic production at at the at the cell in general, so specifically for fatty liver. So we caught we talked about, why endotoxin such ubiquitous poison, some of the mechanisms that it works through. But as far as specific to fatty liver, they've done some interesting studies with fatty liver where they have and they involve germ free mice. So in the germ free mice, they don't have an intestinal microbiome. They don't have any bacteria in their gut, and they don't tend to develop a lot of these metabolic dysfunctions when you feed them alcohol, when you feed them excess fructose, when you feed them excess fats, any of these, any of these type of models that they use in other studies to induce fatty liver and regular RATS, RATS that have micro microbiome. So and one of the studies, what they did was they took the bacteria from people who had fatty liver and obesity, and they put them into germ free mice. And then the germ free mice developed fatty liver obesity and impaired glucose tolerance. When, when they, when they put these, this bacteria in and then when they and those people, when they adjusted the diet a certain way, it eliminated their fatty liver and they lost the weight, or they lost some of the weight. And then the same thing in the rats, when the rats diet was adjusted, even despite having that bacteria in there, the fatty liver was adjusted and it was basically minimized, and then were eliminated, or it couldn't be developed. So it was so to further test this, or I guess before I get to the further testing, it's just important to realize that the bacteria from the from the people who had fatty liver were gram negative when producing large amounts of endotoxin I fed a particular diet. So what they showed here is that the germ free mice, when exposed to this bacteria in their microbiome, were able to develop the same exact pathology, which would point to say, well, you know, maybe this is actually the cause and what's going on with the fatty liver. So they they further further that experiment to see what exactly it was. So in the first in the that was the first phase in the second experiment, they knocked out toll like receptor four in these germ free mice, and the toll like receptor four is the main or TLR four is the main receptor for endotoxin on the immune cells. So basically, recognizes endotoxin. The immune the immune cells use it to recognize endotoxin. Other cells do as well, and then they stimulate this inflammatory response. So when they knocked out toll like receptor four and these germ free mice, despite the germ free mice having this, this non alcoholic, fatty liver disease bacteria in their gut and being fed a diet that induces their production of endotoxin and growth. The mice didn't get the same level of fatty liver and impaired glucose tolerance and obesity when they knocked out TLR four. So what this is showing here is that the signaling of endotoxin in the immune cells from this these pathogenic bacteria in the gut was is what's producing the pathology. So they took it even a step further. And rather than knocking out toll like receptor four in the rats, the germ free rats, they knocked out the bat, the the bacteria's ability to produce endotoxin by inhibiting one of the enzymes that codes for part of the protein in the endotoxin structure. So now the rats the bacteria, couldn't produce a functional endotoxin, but you still had the same bacteria in those germ in those what once were germ free rats with the bacteria unable to produce the endotoxin. The germ free rats didn't develop non alcoholic fatty liver disease. They didn't develop obesity, and they didn't develop any impaired glucose tolerance or anything like that. So what you're seeing here is endotoxin being central to this pathology. And when you look back in the previous part of the study, when they changed those people's diets, they changed the their microbiome, just to some extent, and they're at the endotoxin levels coming from their microbiome. And then those people didn't those people basically eliminated their non alcoholic fatty liver disease. So studies like this are showing that endotoxin is central to this pathology. When you talk about the other pieces that I brought together before, where you see. No toxins, effect on lowering thyroid, lowering steroids, and up regulating glucocorticoids and then signaling fat liver fat production from the liver with tumor necrosis factor alpha and il six, and causing inflammation and then also damaging mitochondrial function, all the mechanisms that we just talked about before, as far as what's causing fatty liver disease. When you look at the mitochondrial dysfunction, the excess production of fats, the excess the exportation of fats, up regulation of glucocorticoids, it's literally endotoxin is signaling all of these processes. So there's a couple, there's another. There's some other, more interesting studies to the other. There's one other part of this germ free study that I want to mention, they, rather than putting in this pathogenic bacteria from these, these, uh, these obese people who had non alcoholic value liver disease, something else they did was they put in another type of bacteria that produced an endotoxin as Well, but the endotoxin had a different structure. So it's, it's inflammatory, function wasn't the same. So the endotoxin has, like a lipid tail, and then it has a o antigen center, and then it has a carbohydrate group attached to that. If you change the structure of this endotoxin, what happens is, it's, it's immune stimulating effects can be modulated. So some bacteria, and some of the ones they mentioned were bacterioids, was a was one of the species this, this species of bacteria's endotoxin isn't so immunogenic, whereas E coli and Klebsiella pneumonia, endotoxin is extremely pathogenic and causes like can cause serious immune stimulation. So the they gave these rats, this bacterioids, species of bacteria and the endo it didn't produce such a potent fatty liver disease, weight gain and impaired glucose tolerance. It was like a portion of what was actually created with the more potent endotoxin. So essentially, what you're seeing is that certain types of endotoxin very potently stimulate this fatty liver profile, and others don't stimulate it quite as much, which basically brings it down into what's going on in the gut. And this is something that's going to be important when we, when we go through solutions in the in a little bit later on, but it's just important to see that now the next study is with alcohol. And unless you want to add anything to what I what I covered in there.

Jay Feldman 37:34
No, I think what we're basically just getting at there are the main pieces of that study are just implicating endotoxin, as, at the very least, a cause of fatty liver. And when the reason why they look break it down and look at each piece individually is to try to identify, is it actually the endotoxin or something else in the bacteria, and what exactly is the endotoxin doing to create the situation? And so what? So, basically, yes, they found based on these this what they did in the experiment, they did find that endotoxin, endotoxin was the culprit in this case, and did so by driving inflammation and inhibiting respiration, which they didn't look at as particularly but that's, I would say, that's underlying a lot of the inflammation as well, and part of why we have an inflammatory sponsor in the first place, but yeah, so that's just to give some context there. And then, yeah, I think it's helpful to go through the alcohol as well. So so go ahead.

Mike 38:29
So the alcohol studies and so in the research, they've kind of differentiated between non alcoholic fatty liver disease and alcoholic fatty liver disease. And they're trying to make as if they're they're two different things. You know, one stimulated by alcohol. One can be one conjure whatever mechanism you want, too much sugar, too much saturated fat, not enough choline, not enough the thigh. Mean, Western diet, whatever it is, but it's all kind of breaks down to the same thing. And as again, they do their studies in germ free mice with the alcohol where, and I think we've mentioned this previously, but with the with the germ free mice, when you expose them to alcohol, the they don't develop the same liver pathology. They don't develop Nash or cirrhosis or anything like that that other rats that had that weren't germ free would have developed. And so basically what they determined was that the alcohol causes the intestinal permeability and allows for the endotoxin to get into the basically get into the body in non germ free rats and cause this dysfunction, whereas in germ free rats, they don't have the microbiome. So even if their intestine gets a little bit more permeable. The only insult that they have to deal with is just the alcohol. So it's not doesn't really cause as much dysfunction. And so it's boiling down to the same thing that the ubiquitous poison here is the endotoxin, and anything that's impairing the gut integrity or changing the microbiome to increase the production of Endo. Toxin, and then subsequent absorption of endotoxin is going to accentuate or increase this pathology overall. And so basically, in some of the liver studies and some of the alcohol studies, what's interesting is that when they feed them saturated fats, the endotoxin production is it or the the damage to the liver is like, like mitigated. It's almost eliminated. So the only thing that you see is that the rats develop fatty livers with the alcohol, and even if they continue to ingest the alcohol, if they have adequate saturated fats, this was either from coconut oil or beef tallow, the rats livers were protected, so they never went into non alcoholic steel hepatitis, which is the inflammatory stage. They just stayed in non alcoholic fatty liver disease. So the liver just held on to the just held on to the fats. And basically this is what we talked about before, the saturated fatty acids, besides changing the actual membrane structure of the cells of the liver and making them less likely to be oxidized from reactive oxygen species. The saturated fats can actually bind the endotoxin as well and inactivate it. So they've done different studies with there's a couple other interesting studies where in patients who in rats, where they exposed them to endotoxin, if they give them bile acids, they give them fats and their intestines before they give them the this oral endotoxin challenge, the rats are actually protected against that endotoxin. And then the same thing, if they inject endotoxin, if they give the rats bile acids and saturated fatty acids, it protects them from the endotoxin. And then in sepsis, if you infuse fats into the into the bloodstream. So that's your like, I think it's like recombinant HDL and LDL, which is the cholesterol. It actually protects the rats or the study population from sepsis, because they bind the endotoxin. So the fats are this, fats can actually be protective. And you see that with the saturated fatty acids the Now, as far as monounsaturated fatty acids, they are kind of like they're kind of neutral. They can be protective, because they stimulate bile acid production, and they form the chylomicrons in the intestine, which are which are helpful, the Omega six fatty acids, they actually stimulate the process, and can make it worse, because of their they are the precursors to inflammatory cytokine or inflammatory mediators, prostaglandins. And then they also can, if they're incorporated into the cell structure, they're easily oxidized. And then the Omega threes, they actually they're kind of weird, because they have, they can have some benefit, because if omega three is incorporate, Omega three can't really be incorporated into the endotoxin structure, to a large extent. And it kind of like, I think it degrades the structure, if I remember correctly, so it actually can have, like, a slight anti endotoxin effect. But the problem is, is if the Omega threes are actually incorporated into the cellular structure. They're more likely to peroxidize the membrane because they're they're so fragile. So it's kind of like a, it's kind of like a with the Omega three. You might not have the dysfunction so much in the microbiome, but if you do have endotoxin and a decent amount and is reaching the liver, you can, you can amplify that damage. And then the last point I want to bring in here with the saturated fatty acids, and some of the studies, they actually are able to induce some of the pathology or increase endotoxin with the saturated fatty acids intake in some of the animals. And What's What's basically happening is that the animals bile acid composition is being changed by the saturated fatty acids, and you get more taurine conjugated bile acids. And the taurine conjugated bile acids can can cause a shift in the microbiome population, the bacterial species, and lead to some producers of endotoxin and not having a gallbladder. This is something that I've experienced myself. But I think for people who do have a gallbladder and their their their biliary and hepatic cycling pathways with bile acids are functioning appropriately. The saturated fatty acids might not be as big of a deal because they're able to absorb their bile acids appropriately and put them out appropriately. But with somebody, when that gets disrupted by removing the gallbladder or something like that, it might cause more of an issue. And the animal models, I think you see this is because their their intestinal structure is set up a little bit different, whereas rats are made to ferment, and we talked about this with some of the fructose and and sugar feeding as well from fruit. So there's a little bit of difference in digestive physiology there. But I think it's just an important caveat to note, because anyone who's like worried about the saturated fat endotoxic connection, that's something that I've seen brought up. So I don't know if there's anything you want me to clarify, or you want to add in, or?

Jay Feldman 44:57
Yeah, so all of these different you mentioned alcohol, you mentioned fructose a bit, which I want to circle back to, and the polyunsaturated fats and saturated fats and their relationship with endotoxin. And these are all those, for example, the polyunsaturated fats and alcohol have their own direct ways of also contributing to fatty liver that are outside of endotoxin. But all of these things are directly intertwined, right? We can't talk, or it's not as easy to talk specifically about endotoxin without also talking about how PUFA will amplify its effects, or, or, uh, alcohol will amplify those effects, or how those things can be mediated by endotoxin. So we'll go through each of those individually and kind of spell it out a little bit more clear just to and talk about some of those other aspects as well that are independent of endotoxin. But yeah, the reason why, maybe not. The reason why, I guess what I would say, is, when we have these things that are generally metabolically a problem, it's no surprise that they're not that they're not independent or not intertwined with or that they are intertwined with everything else. Right in this you know, you talked about the impact of endotoxin on the different hormones, on decreasing thyroid activity and decreasing reproductive hormones, and increasing stress hormones, and those things compound as well. When you have elevated stress hormones for any other reason. For example, they'll also decrease the thyroid hormones and decrease the reproductive hormones. It's we've got these very integrated systems, and they aren't there by accident. You know, the things that happen to be harmful aren't just harmful on one level because our bodies decided they can't work too well with it. You know what instead has gone on is that they've developed not to work with those things because those things cause other problems that are not conducive to having enough energy, into having complexity, into functioning well. So there's a lot of intricate pieces here, but it does it all webs together in the same direction. And, yeah, I don't think I have anything to add specifically on any of those things, because I figured we'll, we'll kind of talk through it, through them in details. We talk about those as their own causes of of fatty liver and or contribute contributions. You know, they're each, each of their contributions to fatty liver. I did want to mention as far as fructose goes, because we talked about fructose very early on in the series, and we did describe there how endotoxin is one of the main mediators between fructose and fatty liver. It's not the only thing in the same way as it's not the only thing with alcohol. It's not the only thing with PUFA, but it is a it's kind..

Mike 47:36
Of central, though it's kind of central endotoxin from alcohol and from the Western diet studies and from the microbiome studies, and from the fructose studies. And no toxin seems to be central, and a lot of these. So while like overfeeding of fructose, just to the liver itself, can you know, in extremely large imbalance without glucose, can cause some issues. The primary meeting mediating effect seems to go through the increase in endotoxin that's and even with alcohol too, like in the germ free rats, like when they're having alcohol, like they had some minor dysfunction, but it didn't progress to Nash or or cirrhosis or anything like that, even while they continue to have alcohol. So the endotoxin, like, I think, is, at least from my, my perspective, my opinion, is central to the fatty liver disease in general and to alcoholic liver disease. But there's other things like depletion of nutrients, and, you know, the actual metabolic effects of these components themselves. But I just think that the endotoxin is kind of like that, that wrench in the gears that starts to really derange a whole host of pathways, and the body tries to start piling on these feedback loops to address it.

Jay Feldman 48:56
Yeah, I see it as a central piece. I just don't see it as as D and obviously, like, I obviously it's seen that when you take something like fructose and you remove the endotoxin component, it's nowhere near as harmful. But that's kind of like, what's a good example? We'll see, I'll see if something comes but you know, anytime that you have multiple bad things, it's gonna be a lot worse than one bad thing. So I think fructose, in the context of a rat who is not healthy, and, you know, and on and on and on, and it's given without glucose and all that, is going to cause a lot of problems. If you have endotoxin there, those problems are just gonna show up much quicker and be much worse. If you don't, I think they'll still end up happening, for example. That's why you can also see the same effect with PUFA, right? We have that, which I'll talk about when we talk about PUFA as well, but we have that study where they just blocked the metabolite of of the Omega six fatty acid. And when they did that, that stops the fat production from the the fructose consumption in the liver of the rat. So I think that you can you. Say this, and we see this when we're looking at saturated fat versus PUFA in terms of of alcohol as well. If you have alcohol plus PUFA, it's way worse than alcohol plus saturated fat. And then, you know, if you have the same way of saying, if you have alcohol plus extra endotoxin, this can be worse than you've alcohol plus not extra endotoxin. So I think, from my view, and you know, if we find like not fully agreeing on it. I see, I just see it as one of those pieces, and a very important one, and a very strong one, and probably one of the main ones that we see in a lot of cases. But I just think it's there are other factors that are like, it's one of the many, and it's one of the most like, most noteworthy. But it's not the only way that things can be, that this can be caused or, like, like, I think you could, for example, have fatty liver without any endotoxin.

Mike 50:48
Yeah, the thing that, and it's all a chain of events, right? Because you have to be, you don't just get endotoxin out of nowhere. You have to be doing something that leads to the endotoxin production. And then you also have moderate, like, there's a what, what shifts from going to non alcoholic fatty liver disease to Nash is in the studies, that we see is excessive reactive oxygen species production with subsequent damage to the lipid membranes of the mitochondria in the cell. And what increases susceptibility to that is PUFA, is polyunsaturated fats. So it's a series of events working together. It's just, I see, like, if you had a fuse and you set up the fuse, all these things would, would, you know, they're like, making that fuse get real close to the fire and very easily, very reactive to being lit. And endotoxin is kind of that spark where it's like, you have, you, take somebody. And the thing is, it's not a perfect analogy, because high amount of omega six consumption can cause dysfunction in the gut and all that type of stuff as well. But it's like, if you have, if you have your tissues loaded up with polyunsaturated fatty acids, and then you start throwing the the endotoxin in there, you just look that you're lighting the match on the fuse, and then essentially, it's everything from there starts to derange and nutrient deficiencies and like, it brings all these things to the surface, which is why I think you see people it's like, I was all great, and then it's like, I hit like 26 and boom. Or I hit 50 and boom. It's like, you recruit all these, these small, minor in the system. And then finally, something happened that set off, set off the the chain of events connecting all of these little together, nutrient deficiencies and no toxin accumulation of talk of toxins in general, whether that's PUFA, whether that's heavy metals, whatever it is, there's, it's that's like, kind of the idea, like the straw that broke the camel's back, right? It's like, right? One little thing kind of snaps off a whole, a whole system that has been slowly deranging over time.

Jay Feldman 52:50
Yeah, yeah, absolutely. Let's talk about how these other factors outside of endotoxin do contribute to the inhibited respiration that underlies fatty liver, and then that leads to the progression to Nash. So PUFA is one of those huge players, and we've talked about this in so many other contexts, and we've done that because it is a really good way to create dysfunction. It's a really good way to block our ability to produce energy, and it does it in a few different areas. I'm just going to breeze through these real quick, because we've talked about them a bunch before, and I'll refer to those episodes but basically, for one, PUFA is very susceptible to damage, and because of that, it will easily become oxidized, peroxidized, and that causes a whole chain of reactions and a whole chain of damage that is problematic, and in a roundabout way, will lead To stress and inhibited respiration. Another thing is, even if the PUFA is not damaged, and again, this is the Omega sixes and omega threes, even if it's not damaged, it is has a high likelihood of being incorporated into the membranes of or like the structure structural components of the cells. And we see that when you eat more PUFA, you get more in your cells. And that again, in that case, it's way more susceptible to damage. But the other thing that it does is it basically increases the leakiness that's going on throughout the energy producing processes, and so that makes our energy production capacities much lower, and creates a lot of inefficiency there. So that's that's one thing. Another thing that it does, too is so the other side of the leakiness is it also increases, and this is called permeability. So it increases proton permeability, which is important for well, is important not to do when you want to increase ATP production. And it also increases permeability to ions like sodium, which is not a great thing, because we want to be able to exclude ions like like sodium and calcium. So that's the second way. And then the third way is that PUFA can be converted to various metabolites, which are called eicosanoids. And there's a few different enzymes that do this, and this results in things like prostaglandins and leukotrienes, and there's several others. And. These basically amplify inflammatory signals. And so when you do have inflammation, when you have stress, when you have damage, these encourage those things to further to they drive them further. And we see all of these mechanisms playing a role in fatty liver disease. There's a lot of and we'll point to in a moment, a lot of research where they see these different mechanisms as as primary drivers of the non alcoholic fatty liver disease state driving fatty liver is there anything you want to add in?

Mike 55:28
I just wanted to clarify what you're talking about. The proton leak. Really quick for people. It's just when the cell is producing energy, it basically, you could think of it like making a reservoir inside, inside the mitochondria, inside the inner mitochondrial membrane. It creates, like a reservoir of of protons, which are H plus ions or hydrogen hydrogen ions. And those protons, you can think basically like, think of like a reservoir for a lake, like it's super filled area, and then at the bottom of the mitochondrial inner inner membrane, there's an enzyme called at pace, which produces ATP. And all basically the ideas is kind of like a hydroelectric dam where the H plus or the protons are able to flow through the ATP at Pace enzyme, and as it does that, it harnesses the electricity, it harnesses the energy and produces, like, uses that energy to produce ATP, ATP. So that's that's so basically, with the PUFA situation, with an excessive amount of PUFA accumulated inside the membrane, it, it allows more protons to leak. When the protons are leaking, you basically can't effectively build your reservoir so you're able to harvest less energy from what you built up. So you're wasting, you're essentially wasting the energy that you're building up. And then on top of that, and I wasn't necessarily wanting to cover this, but since it's right there when you also incorporate the polyunsaturated fatty acids in excessive amounts into that membrane, when the cell when the membrane proteins and the electron transport chain are creating that gradient by moving The the hydrogen ions into the inner mitochondrial lumen. The process of doing that creates oxidation. It create it. It in the oxidation can basically damage the membrane, and if the antioxidant enzymes aren't functioning appropriately, or if there's excessive amounts of polyunsaturated fatty acids incorporated into that membrane. So it's like the walls of the dam. If you have too much polyunsaturated fatty acids in the walls of the dam, or if you basically have like a weak building material of your dam, the dam starts to leak out some water. It'll spur a leak here and there, and then the water inside the dam to some extends on a perfect analogy, is able to, like, degrade the actual structure of the reservoir and the dam overall. That's what happens inside the cell when there's too much polyunsaturated fatty acids incorporated into the membrane, or just in general. So it's that the accumulation of them in that in that space, in that areas, has like a multifold negative effect on metabolism. Now, one thing I want to stipulate here is some polyunsaturated fatty acids are present in some amounts, in the membrane and in some of these components and have some specific function. But it becomes to a question of amount and threshold. And having excessive amount is like a serious, serious issue for energy metabolism. And it also type is important as well. And we're not going to cover that now, but just something to keep in mind.

Jay Feldman 58:57
Yeah, definitely. And so when we're looking at those things presenting in non alcoholic fatty liver disease. For one, you know, I mentioned the eicosanoids, these downstream metabolites of the PUFA. And we mentioned the study earlier, when we were talking about fructose, and why fructose does not cause fatty liver and what they found. And this is one of the, one of the major issues with these fructose studies is that there are a lot of them are in rats, and these rats are consuming a lot of PUFA. And so what they found was that in one of these studies, where they were looking at how fructose causes the production of fat in the liver, they were finding that it stimulates these inflammation pathways, specifically the JNK pathway. And they also found that when you blocked the conversion from PUFA to some of these metabolites, some of these eicosanoids, this didn't happen, and you didn't have the fat production, and this was only by blocking the lox enzyme. So there's also the Cox enzyme, which is another one, and there's a few others that lead to all these downstream products from. To the from PUFA, and just blocking the lox enzyme was enough to prevent the fat production liver in response to fructose. So the they have a quote describing this, and they say that treatment with lipoxygenase inhibitors, which is a LOX inhibitor, reversed the hyper triglyceridemia and also reduced activator protein one activation, suggesting that the basis for lipid dysregulation in this model is due to activation of inflammatory pathways in the liver. So they're just saying that it was the activation of the inflammation and the amplification from these PUFA metabolites that caused fructose to quote, unquote, dry fatty liver. But again, we talked about all these reasons why it's really not the fructose, but they could very well be the PUFA. So that, you know, they mentioned that there, there's a ton of other studies looking at non alcoholic fatty liver disease and finding associations with these eicosanoids, a lot of these derivatives, these metabolites from the PUFA.

Mike 1:00:55
Yep, I think that it, besides just being the PUFA too, like it could also be the endotoxin triggering the expression of the Cox and lox enzymes which are amplifying and basically stopping that amplification process. By number one, you can limit PUFA, and then number two, you can all by blocking the enzymes directly. It basically inhibits the dysregulation that occurs afterwards. So the other thing I want to point out, like there's more at play than just this fructose molecule goes to the liver and then it just causes fatty liver. It's like, there's multiple layers of what's going on. It's like, what else is going with the fructose? Is there some deficiency of some nutrient? Is there some is the fructose not being absorbed and stimulating endotoxin production? Is that endotoxin production signaling the inflammation is the liver already loaded up on polyunsaturated fatty acids. So then you have this, this synergistic effect of excess oxidative stress from the polyunsaturated fatty acids with the inflammatory signal produced from the malabsorption of fructose and endotoxin production on top of nutrient deficiencies. Then it's like, now you have, like, it's always going to be some synergistic effect. It's never just going to be all fructose. There's going to be more going on to the story. That's kind of what I want to get at there. And there's multiple and I that's, I guess we're going to get to today, is there's decided to kind of summarize some of the things that we've gone over, is that there's multiple factors happening simultaneously in these pathologies.

Jay Feldman 1:02:25
Yeah, and looking at the amount of methionine or choline or something like that, these are going to be more those are more affecting that the ability to export the fat, right? And so they're not really going to change the ability, like the capacity or the amount of fat being produced. So in that case where you have those rats, I'm assuming that you have these rats that are being given 60% fructose, which is a huge amount, as you said, even if someone's on a high carb diet that involves 60% of their diet from carbs, at most, they would typically be getting half of that from fructose. So at most they'd be at a 30% fructose intake. And that is very, very different from 60% especially because you need that glucose to properly absorb the the fructose. But even in that case, if, if they're still having that endotoxin, all of that, they're probably still producing a lot of fat at the liver, too much fat. There probably still is issues, right? There probably still are issues with respiration going on at that point due to the endotoxin and all that. But at least in this case, it's not accumulating in the liver due to these other components, but, but that's something that we'll touch on later on.

Mike 1:03:23
Yeah. He also something, I think he also, in that study, they had tested green tea extract in there as well, because it was something his lab was working on. And basically the green tea extract blocked the excess oxidative damage. So the green tea extract, and then also having adequate methionine, you know, was able to entirely protect, if I remember correctly, entirely protect against the fatty liver pathology, which is, you know, very, very, very interesting, and it blends credence to what we're going to be talking about in this episode. And also for everybody out there, because I saw there's comments on the YouTube about like, choline and methionine, we're gonna cover that. Don't worry what's coming.

Jay Feldman 1:04:07
Yeah, yeah, definitely. So, uh, so moving on to some of the other effects of PUFA, and where we see it in non alcoholic fatty liver disease, the capacity for PUFA to become oxidized and drive that oxidative stress is huge, and that's something that's seen very like, seen as a very tight connection between these different types of PUFA and fatty liver disease. So and again, this goes hand in hand with all the inhibited respiration we've talked about, because that oxidative stress will basically prevent respiration from functioning properly. They go hand in hand. And part of the reason for the oxidative stress in the first place is also the inhibition of respiration from the PUFA. So in this study, they were looking at rats, and they they're comparing olive oil to sunflower oil and fish oil. And so they they found that virgin olive oil led to the lowest oxidation and ultra structural alteration. Options, and then in comparison to the olive oil, they found that sunflower oil induced fibrosis, ultra structural alterations and high oxidation, and fish oil intensified oxidation associated with age, lowered electron transport chain activity and enhanced the relative telomere length. So this is just again, looking at liver pathology in rats and giving them different fat compositions, basically high omega six, high omega three, and then a high monounsaturated fat that's pretty low in PUFA, which is the olive oil. And what they found was that the high PUFA, whether it was omega sixes or omega threes, basically induced really severe pathology, fibrosis, ultrastructural alterations, high amounts of oxidation, and also inhibiting the ability to produce energy, lowering electron transport chain activity. So again, all of these things we've been talking about, they're seeing in these sorts of studies, are being directly driven by all forms of PUFA basically,

Mike 1:05:55
Yep, yeah. And then it's so and something to point out as well, the PUFA can directly cause it as well, like, even if you don't like, even if you're do it you're having, you're consuming PUFA, and it's it's not directly causing it, yet, any type of insult that you are going to have or be exposed to is going to be worse if you are loaded up on PUFA. So that's whether, that's whether you have alcohol, if you're consuming alcohol, if you have endotoxemia, if you have acetaminophen induced liver injury, it's just increasing the ability for the different components of the cells in the liver to be oxidized. So it's just, it's like a it's like a pre predisposing effect. And that's, yeah, that's why the goal is, would be to not to not load up on it.

Jay Feldman 1:06:42
No, it's a great point, because in these rats, you're able to look at a rat, a rat's lifespan in a very short amount of time compared to ours. And they were seeing that in all these cases, aging, what they called aging, was leading to liver issues. And it was just a question of, How much was it amplified, or how much was it affected by these other by the fat component. So it's kind of, it's kind of, it's kind of like what you're saying, there's already damage going on. These rats are obviously dysfunctional for whatever reason, because typical aging should not cause this sort of liver pathology. And that doesn't sound like just aging. It sounds like there's deterioration over time. And when that's happening, when you're having some insults, whatever it was that was driving this, the having more PUFA made it worse, right? That's, that's that's what we're saying. It's amplifying that considerably. And and in some of these other ones too, we'll talk about how, I mean, we'll get into, I mean, you just mentioned alcohol. There's several studies that are looking at PUFA versus saturated fat. And then you have this, this, you have this stimulant, like this injury stimulant of alcohol, and you see that PUFA amplify it, make it way worse, or saturate if that protects against it, yep. And this is not to say that PUFA can't also cause it itself. I think it definitely can. But you see it more clearly in this, in this sort of instance, when you're seeing both things together, yeah.

Mike 1:07:53
I think any combination of factors are going to synergize, and you're going to see the effects more rapidly, and you're going to see them stronger. And that's right, whether you're exposed to a toxin, whether you have a nutrient deficiency, what, either one of those, or and, or direct injury, right, which you can go hand in hand with the toxin. But it, it all of it will synergize. And it comes from these, it's going to be these different portions. It's going to be common. You can get technically, consider, depending on amount PUFA to be their toxin, or a or a nutrient, depending on what you believe in that situation, or what research you're looking at. But what it comes down to is you have some sort of deficiency of of certain components, and then having a toxic insult on top of that is just like it's game it's game over. And I just want to point out with the olive oil study, I'm pretty sure that the aging in their livers didn't actually really occur to any large extent, especially in comparison to the sunflower oil and fish oil.

Jay Feldman 1:08:52
Yeah, they said it had the lowest amount. There was still some amount, but it was the least considerable.

Mike 1:09:00
And then the the saturated fat studies, too, that we're talking about, I think that is the you're referring to, some of the Nanji studies. Yeah. So those, in those studies too, the saturated fat protected against the liver damage, and it's still, there was still fat accumulation in the liver, but it wasn't to the extent that it was like, like, destroying the liver, and that was just they were still drinking alcohol. They didn't stop the rats didn't stop drinking alcohol. They continued to get alcohol, and the saturated fat continue to protect them. Whereas the others, I think they compared in one study to fish oil, and I think it was a sunflower, I don't remember those the other Omega six oil that they tested, but essentially, essentially the saturated fat, like they didn't the livers didn't progress to, like, the histological or structural damage of the liver cells. They just the liver cells just increased the amount of fat content. And as we talked about previously, you. Having fat in the liver doesn't necessarily mean that you're going to damage the liver cells. It it's almost it's a protective mechanism for the liver to dispose of the excess substrate that's coming in or that's being created, or a combination of factors. So it's not necessarily a bad thing, and that's why, when you look at non alcoholic fatty liver disease, and for a while, this is kind of like a paradox, paradox in the research, whereas, like, people would get non alcoholic fatty liver disease, and they just wouldn't progress to the next step would be non alcoholic steal hepatitis, which was the actual inflammation of the liver. Their liver was just fat, like their liver were just building up fat inside of it, but it wasn't to an extent that it became to, that it became a toxic issue. Whereas, and I don't know if you're going to get to it, but when they put when they had increased lipid peroxides and oxidative stress from polyunsaturated fats in the liver, in the fatty liver stage is when you start to see people convert into non alcoholic steel hepatitis. So that's, that's, that's another example of just how loading the liver up with PUFA, increasing the damage that can be occurred in any type of insult.

Jay Feldman 1:11:14
Yeah yeah. And as you're saying, it's important to recognize that, you know, you don't want to be in a case where you have fatty liver, but it is protective. It protects against endotoxin, protects against alcohol, protects against, all you know, direct cellular damage and death. And we did discuss that. We talked a little bit about SCD one as well. In that way, where it's it's like, it is protective. You just don't want to have to use that pathway. So, yeah, so, and that's important to note, but right then the concern is, of course, you want like that first level is protection, and if things are not being protected, if you still have this continuous damage and insult, then you see it develop into a much more problematic process, and you see PUFA as being a good way to amplify that and make it worse, and basically act as one of those insults that helps drive it further, drive the pathology further. And so to touch on those Nanji studies, those are, there's a couple of good Nanji studies where they looked at saturated fat versus unsaturated fats in alcoholic liver injury. And so in the first one, they did they so here's a quote. They just say that a diet enriched in saturated but not unsaturated fatty acids reversed alcoholic liver injury. So that's noteworthy, but it's also noteworthy that they used palm oil as the saturated fat there, which is still about 10% PUFA, particularly Omega six. Yeah, yeah. And that was compared with fish oil. But then they did a second study that was looking at they used MCTs, which are fully saturated. And in that one, they say that the data indicate that a diet enriched in saturated fatty acids effectively reverses alcohol induced liver injury, including fibrosis. The therapeutic effects of saturated fatty acids may be explained at least in part, by reduced endotoxemia and lipid peroxidation, which in turn result in decreased levels of TNF alpha and Cox two. So we're seeing decreased inflammation, decreased peroxidation and and reduced endotoxin. And I'll mention a couple more things about endotoxins. That's an important piece of this too, and how they synergize. But what you're seeing here is, again, two mechanisms. On one hand, you're you're seeing less damage or more damage, I guess, if you're looking at it from the unsaturated fat side and more endotoxemia, versus the saturated fat side, you're seeing less of the damage and less endotoxemia and less inflammation. As a result, I know you're saying earlier, as far as like the lox activation, like the or lox activity, the enzyme that's converting the PUFA into its downstream metabolites, that that's going to be affected by the general state, not just the amount of PUFA, but the amount of PUFA matters too. And so here they're seeing that Cox, the Cox enzyme, was decreased when you had the saturated fat versus the PUFA. So it's also you have this positive feedback situation with PUFA, where a you have a greater amount of the signal, because you have a greater amount of the precursor, and it directly increases the activity of the enzymes that cause those metabolites. So it's, it's like, you know, it's like, on all levels, you're seeing this, this, uh, increase in damage and injury and pathology.

Mike 1:14:26
I also, I'm pretty sure there's also a Nanci study where they looked at cocoa butter versus MCT oil as well, to see the different effects with alcohol feeding and the and set the different types of saturated fats. Because you have the coconut oil is, like, is medium, mostly medium chain, and then the beef towel was longer chain. And this goes with, was a beef towel or cocoa butter, or cocoa butter, excuse me, Yeah, I'm pretty sure. I'm pretty sure it was a cocoa butter. It was, it was either beef towel or cocoa butter, because the beef towel or cocoa butter had long changed fatty acids. I'm pretty sure it was cocoa butter. Now I remember it. Yeah, and then the coconut oil, or the medium chain triglycerides, had medium chain saturated fats. And essentially what you saw in that study. And and the reason I bring this up is because a lot of people want to point to that saturated fats increase endotoxin in the bloodstream, and I think we briefly touched upon this earlier in the series. But essentially, in these studies, the medium chain triglycerides actually how helped to keep the the intestinal epithelium like secure from the endotoxin, and then the the cocoa butter bound the endotoxin and basically allowed it to be detoxified by the liver without stimulating an excessive amount of tumor necrosis factor alpha, which is the the main mediator that you just mentioned, that that stimulates this endotoxin exposure and through toll like receptor four, and then you also that the whole pathway up regulates cyclooxygece and lipoxy oxygenase, which are the the enzymes Cox and locks that further amplify that inflammatory response. So what you're seeing with these saturated fats is that they're helping to mitigate the damage from the endotoxin and then lowering what, as you mentioned, by changing the actual disposition of or the state of the cells of the liver, but by also lowering that inflammatory cascade, because they're making the endotoxin and its effects less damaging to the body overall. So it's like there's multiple effects through this situation, and through these, these different fats and and and their their mechanism of action overall.

Jay Feldman 1:16:43
Yeah, well, in another piece we talked about before, in terms of, yes, the increase in endotoxin uptake, you could say with saturated fats is that they're doing it through the chylomicrons, through these lipid rafts that have these protective effects. But one other thing that was so there's a another good study is looking at saturated fat and unsaturated fat, comparing the two in alcoholic liver injury. And what they found, they say that we demonstrate that unsaturated fat they were looking at corn oil or linoleic acid by itself, results in dysregulation of intestinal tight junction integrity, leading to increased gut permeability, and alcohol further exacerbates these alterations, we postulate that elevated blood endotoxin levels in response to unsaturated fat and alcohol, in conjunction with upregulation of hepatic TLRs, which is the receptors in response to endotoxic receptors, yep, yep, combined to cause hepatic injury and alcoholic liver disease. So here we're saying another way is that instead of having the the protective kind of lipid raft mechanism with the endotoxin here, instead with PUFA, seeing increased intestine permeability, causing basically a huge influx of flood of endotoxin, plus other things not bound to the fat, which detoxifies it to saturate fat, specifically, yeah and yeah. So that makes all this worse. So there's a good example here of if the saturated fat was was causing a problem by introducing or in like increasing the uptake of endotoxin through these lipid graphs, then you would see it having a much worse effect than unsaturated fats. In this case, which is a case where you're seeing elevated endotoxin as a like already, we know that that's a huge mediator. We we talked a bit about it, about how alcohol induces non alcoholic fatty liver disease, bioregulating endotoxin uptake essentially, or, you know, increasing leakiness into the Yeah, yeah, yeah. So in a situation, we're seeing that the most you would expect, that if saturated fat was really worse for that problem, it would definitely be making this way worse. And instead, it's not it's protective, and the unsaturated fats do the opposite. They make it all worse so.

Mike 1:18:49
Yeah, and I don't know if I mentioned it previously, but there's a study literally showing that the subjects, who it that I think they were, it was either diabetics or and compared to different groups, but when they they were taking in cream, which is mostly saturated fat, the large amount of palmitic acid, they had higher levels of serum endotoxin. But the the endotoxin wasn't stimulating the inflammatory effect because it was bound to the lipid rafts that were being brought in, brought into the body, and essentially being detoxified before it got there. So if you have, you can imagine, and we're talking multiple mechanisms so far. If you have, if you have the saturated fatty acids going into the system, they bind up the endotoxin and basically move it into a largely inactive state that doesn't really stimulate the inflammatory response quite as much. They stimulate bile acids in the small intestine, which did basically destroy endotoxin. They stimulate alkaline phosphatase, which is an enzyme that also destroys endotoxin. And then they also can increase tight junction or the. Area of the small intestine, and then they also aren't causing oxidative stress. So you have multiple mechanisms where they're protective. And then the other thing is monounsaturated fatty acids. They they basically aren't increasing the endotoxin, and then they are, they are stimulating the bile acids, and then they aren't increasing the oxidative stress as well. So both monounsaturated and saturated fatty acids are extremely protective in these states. The saturated fatty acids, as we kind of mentioned previously, is there a little bit harder to process because of their saturated structure and the triglycerides that are formed in the liver to export fat or in whatever mechanisms is required to move the fat or process the fat. Saturated fatty acids could be a little bit more difficult to deal with if there's a large, large amount of them, whereas monounsaturated, the body will literally take the saturated and convert it into monounsaturated to to process it better. So it's it's like, if you know, I guess a good example for the processing issue is if we had to move a whole bunch of a material, it's like if we could just build a slide, and if it was in liquid form, it will just go down the slide, versus if we had to carry all of it, it, it changes the it changes how we would move it, how we would process it, because the carrying form is extremely solid and heavy, whereas if the the liquid form, if we have it in a more liquid form, we can just kind of move it more fluidly. We can create mechanisms to move it more fluidly. So that's kind of the difference, but in those so those, those are the, I'd say, the nuances between those two fats. They do they but they both have some protective effects. The real issue comes when you have an excessive amount of polyunsaturated fatty acids being incorporated into the actual cellular structure, increasing oxidative stress. And the thing is, is, in some studies, they don't increase oxidative stress directly, but that also depends on the state of the body. And so if the body is in an inflammatory state, like fatty liver disease or any or diabetes or whatever else, throwing something that's extremely likely to oxidize on top of that, state is is not great overall. And again, the the lack of increased oxidation are generally, um, short term type of situations. So, yeah, I just want to put that stipulation I saw your face. There's a basic and then you have, like, some mechanisms talking about increasing tight, the tight junctions, and then also being precursors to inflammatory mediators overall. It's just not a great picture for the polyunsaturated fatty acids in a lot of these disease processes. And then, even more so, and this is tangential getting to it, but that oxidation extends outside of the cellular structure, where, if you have the higher amounts of linoleic acid, which is omega six polyunsaturated fatty acid incorporated into cholesterol to be exported from from the liver, in this inflammatory state, like non or like non alcoholic fatty liver disease, you can get increased risks and damage to the to the vascular the vessel walls, due to oxidized cholesterol, oxidized LDL. So there's, like, on multiple fronts, it's not good. And then I guess I'll there's another front there that I want to talk about, which is cholesterol production. But we'll leave that for a little bit later on, because we want to dig into, like, wrap up all the different mechanisms that we just covered in these past few episodes.

Jay Feldman 1:23:25
Yeah. And so just a couple of things. So you mentioned the tight junctions. I just wanted to clarify that the unsaturated fats are decreasing the tight junction integrity.

Mike 1:23:35
At least it would be omega six Cornwalls were specifically decreasing, yeah, yeah.

Jay Feldman 1:23:39
I think you said increase. I think it was just, I think you just,

oh, okay.

So yeah, just want to clarify. And then, yeah, so you were saying short term, some of the unsaturated fats can decrease inflammation. Long term, they end up making it a lot worse by inhibiting, you know, all the, all the mechanisms we talked about in inhibiting efficient respiration, being susceptible to damage, increasing the carcinoid, all those things. So just again, when you're seeing that, it tends to always be a short term versus long term. Versus long term situation, and that's why, when you do see these studies, it's very clear that they're not really increasing or they're not really relieving any amount of oxidation. They're not really decreasing inflammation at all. When they are doing it, that's coming at a cost, and it's not going to last. Yep. So I think we hammered the point home with PUFA. I wanted to talk about just a couple other more minor things that are also involved in inhibiting respiration and driving oxidative stress and driving the underlying pathology of non alcoholic fatty liver disease and virtually every other issue that we discuss all these other symptoms and conditions. So one of those is nutrient deficiencies. And there's a lot of places that nutrient deficiencies play a role in fatty liver and and you kind of alluded to those earlier. As far as something like choline goes, we'll get to go to those later on, when we're talking about the ability to export fat. But as far as the direct dramatic increases in. The production of fat due to the direct impediment and respiration. There are some nutrient deficiencies that can really contribute there or or even nutrient excesses, if you call them nutrients. So one would be the B vitamins, and those are incredibly important for various pieces along the the energy producing chain. So if you're deficient in those, that will lead to some inhibition of respiration, and it can also force fatty acid oxidation. For example, if you're low in thiamine, that's going to be one of those main switches that that allows for carboxidation. So that would force you into fat oxidation. If you're low in b3 which is niacinamide, that's going to decrease NAD that'll do the same thing. We've talked about those things before. There's a bunch of other places where B vitamins play roles in respiration. It includes b2 and includes biotin, several others. So b5 so those are going to be another factor. Additionally, things like magnesium are necessary for respiration, copper and so if you're deficient in those that those can also contribute to this, to these problems, if you have excessive amounts of iron, that'll directly cause these issues, like impede respiration, and then also, much like the polyunsaturated fats, kind of works in a synergistic way to drive oxidative stress and inhibit respiration. So there'll be a few things again. These are these can be relatively common, these sorts of deficiencies, so they're worth noting, for sure. But as we kind of talked about earlier, I would say that they're relatively minor compared to things like endotoxin and PUFA, but they're absolutely worth considering. And the other side too, is not only the deficiency, but if you have a sufficient amount, or more than sufficient amount, they can help to counteract some things that might be inhibiting respiration. So it is really important that's where you see therapeutic effects of of high doses of some of these B vitamins, and we'll talk about that later on as far as supplementation goes. But you do see therapeutic effects from high doses here. So So that's worth considering as well.

Mike 1:27:04
Yeah, I think that, I think that the inflammatory states that that you find yourself in actually in help to further induce the deficiencies, right? And then this the what led to the inflammatory states to start further enhances or further or cause the deficiencies in the first place, right? A lot of the a lot of the diets that are inducing fatty liver disease are usually like high refined carbohydrate diets in conjunction with high refined fat, usually some type of corn oil, soybean oil, whatever, whatever type of oil diet and and like basically junk food diets, which are the epitome of ox first of all, you're already taking in oxidized and I'm talking about in humans now. So basically the associations that you see in the studies. And then if you look at the trends and disease processes over time, and you look at consumption over time of the different the different fats in the diet and different components the current American diet moved from eating like larger amounts of saturated, monounsaturated fat sources, dairy, fruits and vegetables, potatoes and what was the other like unrefined grain products to highly refined grain products, soybean oil, margarine, decreases in dairy decreases in animal protein consumption in over time in general. So you're seeing like the diet that I that, and I think that's often associated with the non alcoholic fatty liver disease and diabetes is like a fast food, junk food type of diet, which is oxidized vegetable oils with refined starchy products and and, I mean, that's kind of the gist. And then, like a lot of sugar sweetened beverages with no nutrients at all, with high fructose corn syrup at different percentages. So it's like the perfect storm for blowing up your liver. And so you have, like, a lack of copper, manganese, lock, lack of copper, manganese, iron, all these different components that are necessary for your catalase enzymes and your superoxides and mutase enzymes and glutathione peroxidase. These are all the antioxidant enzymes that function inside the mitochondria. Then you have the decrease in magnesium, which is important for energy production, so in a whole host of the antioxidant enzymes as well. And so you're like, you're just driving in this pathology. And then when you get to the inflamed state. It synergizes with that, because the inflammation increases the requirement for these different nutrients. And the other thing is also B vitamins. A lot of the the refined products are fortified, because if they weren't, the deficiencies would be like blatant like straight up beriberi and pellagra, which is. I think b1 and b3 deficiencies. That's why these, these things are fortified. Um, so it's and even then, like, there's still, I'm I would still bet that despite the fortification, people are still having subclinical deficiencies, especially under the inflammatory states. And one note I want to mention on iron is iron is kind of a double edged sword, because a lot of the enzymes in the body require and utilize iron because, because of its ability to oxidize different things, it's often used as a catalytic element, and that's what a lot of the different elements do. The protein has a center core of the element which protects it, whether that's iron or copper, like cytochrome c oxidase, which is one of the main respiratory enzymes, is copper in it the and then they use that oxidative potential of the mineral. They harness it to increase the speed of a reaction. It's actually kind of genius. It's really awesome. But in the inflammatory states, and if you're eating a lot of refined goods with with reduced iron, which is essentially iron particles, just like, like iron flakes in your food. Um, then you you have, you can have serious issues with the iron metabolism, where you can get into, like, anemia of chronic disease, where the inflammatory and oxidative straight state it in the body, forces iron into ferritin, which is the storage form to protect the body from the excess oxidative stress that iron can produce. Right? So it's like, that's a perfect example of what happens with mineral metabolism during these pathologies. It deranges it. So there's like, there's people who will, who will come and they have anemia for years on end, despite supplementing iron. And the problem isn't necessarily that they're low on iron in general. The problem is that their eye, all the iron that they're taking in is being sequestered because of the inflammatory state. And so then when the iron sequestered it, it's again, it's a protective short term mechanism, but in the long term, if you can't get iron to to be used in the specific necessary enzymes for antioxidant function, for hemoglobin, which carries oxygen, for for the respiratory enzymes in the electron transport chain, then now You've just destroyed the entire energetic process, which was initially the protective factor holding up the entire system. So it's really important that that the like that minerals are and nutrients are looked at as well. But this doesn't mean that you need to go and supplement like the multivitamin 5000 what it means is that you need to lower the inflammatory state by avoiding the toxins, and then like have a more nutrient dense diet to rectify what's going on, and the nutrient dense diet often goes with correcting the pathology, right? So, and some of the studies that showed increased serum endotoxin after high fat meals, that effect was completely abolished by adding orange juice to the meal. So, like, you have, like, all these things, all the beneficial stuff synergizes as well. So it's like having a meal that is, that is, like, I don't know what would be, what a meal I'm thinking of like what my girlfriend had for dinner last night. It was like some steak and some mixture of pomegranate or and orange juice, and then she had some cooked carrots on the side with macadamia oil drizzled on top. It's like all of those factors are medicine, and they synergize together, and they're protective against the entire pathology. They lower endotoxin, they provide adequate amount of protein, amino acids and nutrients, and then they provide adequate nutrients for energy production. So it's like, those are the solution. That's like moving the solution is moving opposite of having this, this synergy of just crap food, which is essentially what it comes down to, despite all these articulate mechanisms and whatever else you want to go through, like the actual and the actual solution process goes to be, you know, relatively simple and straightforward to some extent.

Jay Feldman 1:34:08
To some extent, of course, there's,

Mike 1:34:10
There's nuance.

Jay Feldman 1:34:11
Just eating a healthy diet is not a simple, is not really a simple, uh, recommendation, right? Because that looks very different in in all that, you know, depending on who you talk to, and that's part of why we're digging into the details here, is because that will, you will help to also elucidate why something like a low carb diet, which we already talked about, would not be a good idea, or something like intermittent fasting.

Mike 1:34:30
Yeah, there's definitely, there's definitely some, I guess, discrepancy or confusion in areas for people on what's considered a healthy diet.

Jay Feldman 1:34:37
Yeah, and lifestyle too, Right? Like hours of cardio day, you know, on from there, but, yeah, so, so, yeah, I think that's a great way to, you know, encompass the ideas as far as nutrients go and their their role here, to wrap this up, there's, there's one other thing. So we've been talking a little bit about alcohol liver disease versus just regular liver disease. And you know what we're basically talking about is, is that alcohol is just a good way to cause fatty liver and the progressions from there like it is, the mechanisms are no different. It's just uniquely capable of driving those mechanisms. And we talked about how one of those reasons is due to endotoxin, where alcohol is very effective at increasing endotoxin production, at altering the gut microbiota in order to do that, and increasing intestinal permeability, and also it also causes some direct liver issues that impede the ability to handle that endotoxin. So one of the things that they'll do is is that they'll basically because of the way that alcohol is metabolized, which people it's insane again, to compare it to fructose, because, for one, fructose directly rescues and and does the opposite, essentially, of what alcohol metabolism does, where fructose will double the clearance rate of alcohol, and alcohol has been shown to reduce that NADH NADH ratio. It's been shown to cause ATP depletion, whereas fructose has been shown to reverse those things, even though, in and again, they show there's a couple of these studies that people point to where fructose and a super high amount will deplete ATP but those are really just kind of entirely irrelevant.

Mike 1:36:18
Even in those studies, it's only transitory, because I've worked through those studies. It's a transitory depletion. And if you I think, I think Hans an article on it where he, like, compared to pathways between glucose and fructose. And what he eventually showed was, and we, there's like a thread on the form about this with Amazonia, and then Hans and and then I think I was talking about it with them too, and it was essentially like, while you may initially have a slight depletion of ATP from fructose overall, there's not an actual difference in ATP production. It's not like fructose increases the need for ATP over glucose. It was just because of the slight difference in metabolism, because of structure. There may be a period of time, if you like, super load the liver with fructose that in isolation, that you can have some depletion, like transitory depletion of ATP.

Jay Feldman 1:37:12
Yeah, which it just has to do with the fructolysis pathway, and fructose, you know, into the glute, into the glycolysis pathway. It's, it's, as you said, very transient. There's, you see that in the metabolism of other things, like, even throughout the glycolysis pathway, there's parts where you, you like, quote, unquote, deplete ATP. You use ATP to push it down. But big picture, when you fully oxidize glucose, you end up with a far net positive ATP. It's, it's definitely, you know, it's very much the same thing with fructose. So yeah, if you it's like, if you want to isolate one step of like, a 30 step pathway and say, This is what happens, then yes, you could say fructose depletes ATP, but it's, it's entirely irrelevant. So yeah. And so we see these, but in contrast, we see these direct effects of alcohol. These directly liver toxic effects in that it does actually deplete ATP long term. It does reduce the NAD to NADH ratio. It does, you know, we talked about the effects with endotoxin. And it also leads to basically insulin resistance and inhibits proper respiration. Another thing that it does pretty effectively in talking about nutrient deficiencies, is it depletes various B vitamins in order to basically metabolize and get rid of it and so, and these are some of the most important B vitamins. So again, alcohol is just uniquely effective at driving all of the pathways that drive fatty liver, but those pathways are the same. And so there's nothing particularly unique about the pathways. It's just that liver is really good at it, but you can do all those things without alcohol, just like we've been discussing. So, yeah, just wanted to mention that. And then the other thing too, again, just talking about, just to round out, just to make sure that we're touching on this other piece, anything that is going to inhibit respiration will be contributing to this pathology. We talked about some of the big ones, psychological stress in that it depletes energy elsewhere, not directly in the liver, but then drives stress hormone release and will indirectly lead to stress and energy depletion at the liver. Is another good way to drive these processes, fasting, we talked about that, how that can contribute low carb diet, same thing, starvation, essentially, right, right? Excessive exercise too, which I know I mentioned, like the chronic cardio situation, basically what you're doing is you're using a ton of energy. It's concentrated in the musculature. But those we've talked about this in the past with the core cycle, those end up stealing that energy back from the liver. That's, that's, uh, basically where it has to come from. It's, it's not like it's just isolated to the muscles. And so that will, if you're not refueling, well, you'll end up in a stress state that will drive pathologies like fatty liver. So yeah, so anything that's inhibiting that process, which is what we talk about all the time on the podcast, will contribute here. And so, yeah, that's what you see with with the fatty liver situation. I just wanted to make sure that we didn't discount. All these other factors that, while they don't need to be highlighted as much in the situation, are still always going to be factors, driving, driving, inhibited respiration and driving, the sort of pathology.

Mike 1:40:10
Yeah, they all work. It's like, it's not one factor. They all work together. And it's like, kind of hard to it's like, kind of, it's kind of hard to separate anything from each other. It's like the inflammation from the polyunsaturated fatty acids, and in excess of them, can drain metabolic energy production. And in that process, it starts to waste nutrients, and then it opens you up to a whole host of attacks from like say, it starts to impair gut function, whatever it is. And then now you have the impaired gut function with the lower metabolism, all impacting the liver simultaneously and the nutrient deficiencies. So it's like they all and different people's causes for their liver issues can come from different areas. So like, while some person it could be alcohol, another person it could be because they like to eat. They like to eat fast food, three meals a day, another person because they have an extremely nutrient poor diet, particularly like protein and then maybe choline. Another person, it could be because their their diet is very poor in B vitamins. Another person could have been exposed to some other toxin besides endotoxin that, like, what is it? Aflatoxin, from from grain, from a like fungal infested grains, moldy grains, or moldy food, or something like that, could have gotten liver damage from that and started a pathology around there. Like they all, they all come from different areas. Like you can have a different initiating factor in different areas, but they flow through similar pathways, and they synergize in similar mechanisms. And the essential idea to rescue is to eliminate the insulting factor and then provide the nutrition necessary to rebuild the system, and then provide components like some of the the flavonoids and polyphenol compounds to protect the liver from maybe the oxidative stress, or even if that's vitamin C or vitamin E. And that's why you see studies like Oh, vitamin E and testosterone, which is that was a study that Georgie had talked about, like, for rescued fatty liver disease. It's like, well, the testosterone can can block some of the effects of cortisol, and then the vitamin E can rescue the oxidative damage, and then, oh, a high protein diet versus fatty liver it's like, yes, now you're providing adequate amino acids for detoxification, and also for synthesis of choline and and whatnot. So it's like there's a whole host of different ways to go about it. What we're going to do, and I guess I'll telegraph it a little bit, is when we get into our solutions episode, it's like we're not going to hone in on like, you just need to do this. This one Pat, this one thing, it's going to be like, here's a series of things that will synergize together to do simultaneously. And again, it comes down to lifestyle and diet modification. There's like, I don't think, and you know what, at some point, maybe I'll be wrong, but I don't think there's ever going to be some, some quick fix, Silver Bullet drug that's going to manipulate one step in the pathway and cure the whole disease process, like, even, right?

Jay Feldman 1:43:03
It can't. Those come at a cost. We've talked about that, yeah, when you try to do those things, these are protective mechanisms. So there's, there's, there is no successful way to do that, that it's all synergistic, it's all it's systemic, it's holistic. If you try to block that one pathway, there will be a huge cause.

Mike 1:43:20
Yeah, and even so like and like, I think we talked about this. Well, yeah, we talked about this. At one point. There was studies talking about DNP, dinitrophenol. We talked about that where, essentially, it will up regulate uncoupling. So if you have it fatty liver, if you have diabetes, if you have obesity, it'll cause your cells to just burn through all of that excess energy that's stored. But the problem is, is that you're doing that with an energetic deficit. So you don't have you're not producing energy at the cell now and then, these people in these states, these people are already are at energetic deficits. I think that's something we talked about, where the cell is at an energetic deficit, despite having adequate substrate, it's not producing adequate energy. It has adequate substrate. It needs to do something with that substrate. So it's gonna, oh, I'm gonna shunt it into fat. I'm gonna shunt it into whatever it's like, yes, taking DMP and burning through all the excess substrate will show okay. Now you have less liver pathology. You have decreased fat in the liver. You have less fat mass on your body, but it hasn't corrected the actual underlying causative agent, and it also hasn't corrected the entire pathology. Could it help in these situations? Perhaps, sure, but it's not. It's not the one thing that will that solves all of the problems that you still if you have a nutrient deficiency, burning through all your stores through uncoupling doesn't solve that problem. If you have excess oxidative stress, because your your liver is loaded up on high amounts of polyunsaturated fatty acids, burning through your excess substrate doesn't solve that excess oxidative stress. So it's there's like you have to address it. From the multiple angles. And again, I'm not saying to use DNP, it's an illegal compound, and just using it as an example of things that some people have recommended, or some people are talking about, or even some researchers in PubMed are talking about it as a as a strategy. So yeah. And again, the other thing is, like, what like, you have to look at what the actual problem is, to look at the outcome, because just clearing the fat from the liver, while you don't have the fatty liver anymore, doesn't necessarily mean that you solve that pathology.

Jay Feldman 1:45:32
Exactly. yeah, so that's what we'll we'll wrap up this series in these next couple episodes by talking about those things, talking about how to actually address these underlying issues, and now that it's clear what those underlying issues are that are all going through these same pathways, that we're seeing the same metabolic problem, the same energy failure, yeah, all right, that's going to wrap up part five of this series. Make sure to tune into Part Six, where we'll discuss how our livers export fat, and how this exportation of fat can be blocked in non alcoholic fatty liver disease, so we'll be digging into that pathology. If you did enjoy today's episode, please leave a like or comment. If you're watching on YouTube and if you're listening elsewhere, please leave a review or five star rating on iTunes. All of those things really do a lot to help support the podcast, and are very much appreciated. To check out the show notes for today's episode, you can head over to Jay Feldman wellness.com/podcast where you can take a look at the studies and articles and anything else that we've discussed throughout today's episode, and if you are dealing with any low energy symptoms, whether that's any of the symptoms or conditions we've been discussing throughout today's episode, like fatty liver or insulin resistance, or related conditions like diabetes or heart disease, or if you're dealing with any other low energy symptoms, maybe that's chronic cravings and hunger, low energy or fatigue, chronic pain, weight gain, brain fog, poor sleep, digestive issues or inflammation, or any hormonal imbalances, or any other chronic health conditions like autoimmune issues. Then head over to Jay Feldman wellness.com/energy where you can sign up for a free energy balance mini course, where I'll explain how these different symptoms and conditions are really caused by lack of energy, and I'll also walk you through the main things that you can do from a diet and lifestyle perspective to maximize your cellular energy and resolve these symptoms and conditions. So to sign up for that free energy balance mini course, head over to Jay Feldman wellness.com/energy, and with that, I'll see you in the next episode.