Robert Lustig on Fatty Liver, Sugar, Metabolic Syndrome, Ozempic

Welcome, Dr. Lustig. It's a pleasure to have you here today. We're excited to welcome you back to Emory Pharma. So a few months ago, you were here, you were talking about non alcoholic fatty liver disease, and the response was really incredible. So we wanted to sit down with you today, go over some of the questions that came up, and then also some hot topics, some burning questions that we know our viewers are wondering.

So my pleasure, Ana, fire away.

Thanks for being here. So one of the things that I've been wondering personally since you were last here and talking about non alcoholic fatty liver disease, is that how is it that some individuals are considered obese but they're metabolically healthy? How does that happen? Is it a factor of their metabolism being slow? Is it thyroid hormones? Are there other hormones at play?

It's probably not specifically hormonal. What I can say is the people who are obese but not metabolically ill, they maintain their insulin sensitivity. Now, your fat tissue wants to store fat, okay? It's what it was designed to do. It has a job to do. It wants to put it there. It's your spare tire. It's your rainy day, you know, allotment. That's where you want to put excess weight in your subcutaneous or big butt fat, if you will. So big butt fat is, shall we say, cosmetically undesirable, but metabolically inertia, it is actually protective, right? And ask any little old lady who breaks her hip if she wishes she had another layer of fat, okay? In fact, the more subcutaneous fat, the longer you live, believe it or not. All right? So that fat is actually good fat. Now, why is it that some people lay down more of that and some people lay down less of that? We still don't know for sure. We know that there are certain transcription factors involved in fat cell development, and it might be that some people have a greater predominance of those transcription factors driving that fat cell development. And that usually occurs prior to age 2. That occurs in the fetus, it occurs in the newborn. It may be genetic, it may be epigenetic, that is, various things that happen while you're still in the womb. And what we've learned about epigenetics is that they can be passed down from mother to offspring not because of a change in DNA, but because of a change in the expression of DNA. So when you actually look at the genes and do genomic analysis, you don't see anything. But in fact, the epigenes turn it on. Histones are, you know, Opening, closing, allowing for certain proteins to be transcribed at a greater or lesser rate. And that can be passed down at least four generations, if not more. Right now, the other fat, and by the way, when you eat, that's where insulin wants to put the energy in that subcutaneous fat. So some people maintain their insulin sensitivity. They can grow that subcutaneous fat, no problem. Other people have a smaller subcutaneous fat store. This is particularly true in East Asians. And so they don't develop subcutaneous fat stores to any appreciable amount. And so then when they need to store extra adipose tissue, they don't have the fat cells to do it becomes visceral. Then it becomes visceral fat. It can be laid down in the belly instead. Increased visceral fat. Now, the thing that drives visceral fat accumulation more than anything is stress. Stress drives visceral fat accumulation, and it does it through two separate mechanisms, both related to stress. The first is cortisol, the stress hormone. So the adrenal gland makes cortisol, and cortisol drives metabolically active fat, that is visceral fat accumulation. Okay, Cortisol does that. Cortisol doesn't do very much to the subcutaneous fat. If anything, it actually causes subcutaneous fat to be depleted, Depleted, release, depleted. Like we see in Cushing's syndrome, right?

Your body goes into, like, fight or flight. A little bit.

A little bit. That's right. The second mechanism, aside from cortisol, is the sympathetic nervous system. Now, normally, when the sympathetic nervous system gets activated, you release norepinephrine or epinephrine, and that would go to the fat tissue, and it would cause fat release. It would cause you to lose lipid, it would cause you to lose fat. And then those fatty acids that would be released would go to the liver. The liver would turn those into ketones, which we'll talk about today. And then the ketones could be used for energy without insulin. That's sort of how it happens. Now, when the sympathetic nervous system is chronically overstimulated, not only does it release norepinephrine, but it releases a second neuropeptide called neuropeptide Y npy.

And those two go hand in hand.

And those two go hand in hand. Every neuron that releases an adrenergic also releases neuropeptide Y. Turns out neuropeptide Y is the break. It actually stops the norepinephrine from working. It actually tells the target tissue, don't take any More norepinephrine hits.

It's trying to save you a little bit.

Trying to save. It's actually trying to protect the neuron from dying. And so what happens is it turns that neuron off. And so in the case of the adipocyte, it actually then instead of promoting lipolysis, instead of promoting giving up your fat, it actually promotes lipogenesis and start accumulating fat. So chronic stress through both cortisol and through NPY will actually turn a fat giving machine into a fat production machine.

Got it.

That fat, that visceral fat, is particularly egregious because it goes straight to the liver through the portal vein. So a low concentration of fatty acids will end up yielding a high impact on the liver. And then you end up with metabolic dysfunction.

Right.

And then finally the third fat depot, liver fat. And that's what I talked about at the last talk a couple of months ago. And what is the driver of that liver fat? Alcohol and sugar. So stress Alcohol, sugar, particularly egregious in terms of the two fat depots that cause the most damage. Calories. Well, that drives the fat depot that does the least damage, but looks the worst in a bathing suit.

Right, that makes sense. You touched on this a little bit, but with the transcription factors and whatnot. But what are the other genetic factors, factors at play in non alcoholic fatty liver disease?

Well, there are a few Latinos have two polymorphisms in their liver that ultimately lead to increased deposition of liver fat and increased conversion of fructose to liver fat. The names of those two polymorphisms, one is called PNPLA3. First one, it's called PATATAN, like fat phosphoprotein domain A3, PNPLA3. And the second one is called SLC16A11. Now, both of these are involved in triglyceride synthesis. And when you have these two genetic polymorphisms, a little sugar will make a lot of liver fat. And this is particularly predominant in Latinos. And about 18% of Latinos have this problem.

Oh, wow. That's quite a bit.

It is quite a bit.

So that makes sense. So I know that you mentioned this, I think, in your previous talk as well, but you know the old saying, you know, you are what you eat. You kind of modified it. It's, you are what you metabolize, you.

Are what you do with what you eat, therefore, you are what you metabolize. But in my book Metabolical, I made it very clear, actually, you are what they did with what you eat.

Got it.

Because what they did was they altered the food in such a way as to alter your metabolism.

That's very interesting. It's definitely a new take. But it makes a lot of sense. I mean, you are what you take in and you are what's in your body. So.

Well, I mean, ultimately you are what you breathe.

Right, Right.

Air pollution plays a role in this.

Right.

You are what you drink because there are obesogens in the water like pfas, polyfluoro alkylated substances like Teflon.

Right.

Which never goes away.

Yeah, they're ddt.

Right. Ddt, the very first insecticide, first mass produced insecticide. We learned, I mean, Silent Spring, Rachel Carson, you know, 1962, you know, seminal tome on this issue that really brought environmental science to the forefront, documented the problem. And we banned DDT in 1972. So it's over 50 years since DDT has been around. But you can still measure dde, which is the metabolite of ddt. You can measure levels in the urine of pregnant women here in the Bay Area, and the level of that DDE metabolite predicts obesity in their offspring at age 5 years and 10 years.

Oh, wow. So these environmental chemicals are actually predisposing you to potentially becoming obese.

Absolutely. So we have a whole cadre of environmental obesogens, and we've written several papers on this, most recently in biochemical pharmacology. We have another one coming up soon.

And are any of the preservatives that you're seeing now nowadays in foods and chemicals, are any of those contributing, you would say, to obesity?

Absolutely. So there are many things in the food. There's many things in the food packaging. Several things in the food that can drive. This one is phthalates, which are plasticizers. I mean, they're what, rubber duckies? They're what make rubber duckies rubber. Okay. Because they're not rubber. They're plastic. Right. But you know, they. They squeeze. Right. Pacifiers are made with phthalates. Okay. Flame retardants, PBDEs. Okay. So every kid is bathed in PBDEs because it's part of their pajamas.

So how do we stay away from these?

Well, you need regulation, Right? How can you do this without regulation?

Exactly.

And we don't have it. And it's one of the things we're calling for, we're trying to advocate for. There are many, many others. You know, I can go down this parabens, okay, which are in cosmetics, shampoos, shampoos, lipstick, etc. Okay. There's a whole host of these environmental obesogens. And several of them, not only do they affect adipocytes, but they also affect the liver. They can affect ppar gamma, which is the adipocyte differentiating factor, or they can affect FXR and lxr, which are the liver differentiating factors. Some are both. And they're all around us. I'll point everybody to our paper that I'm first author on in Biochemical Pharmacology 2022.

Okay, yeah, we will take a look. That sounds very interesting. Well, as clinicians, we're kind of tr. At least I feel like I was trained at UCSF to treat disease states, and rarely do they train you to treat things before. While they're on the horizon. What would you say to clinicians that are interested in looking at specific biomarkers or things that are indicative that non alcoholic fatty liver is on the horizon?

So, Anna, you've just opened up the biggest can of worms in medicine, all right. And it's going to be really hard to stuff the worms back in now that you've broached the subject. All right. In. In Peter Attia's book Outlive, he describes medicine 1.0, which was basically, you know, the leeches. Okay. And medicine 2.0, which is, you know, penicillin in our current pharmaco, you know, therapies. And now he talks about medicine 3.0.

Very predictive, very preventative.

Predictive precision and also preventative. Okay. Stop the disease before it starts, understand the root cause, and deal with that instead of trying to deal with the symptoms down the line. That's right. I completely, wholeheartedly agree with that. Okay, so how do you do that? Easier said than done, of course. Well, we know certain things. We know that there are certain biomarkers that will tell you that a disease is brewing before the disease actually occurs.

Like insulin levels?

Yes, like fasting insulin. I think that's the most appropriate. I think that's the best one in terms of understanding what the problem is. If your mitochondria are working properly, your fasting insulin is low, like below 5 micro units per mil. The minute your mitochondria start having a burden and not being able to process energy at the rate that it should. Insulin's trying to get more energy into the cell in order to generate more ATP. But the mitochondria are the problem. So fasting insulin is the reflex on inherently problematic mitochondrial functioning. So you can see that fasting insulin rise, and when you see that fasting insulin rise, you know, you have a problem, and you know that you could fix it now before it becomes a big problem later. But the American Diabetes association says don't draw fasting insulin.

Right. And it's rarely, you know, ordered and covered.

Exactly. So this is one of the things I'm trying to fix.

Any other biomarkers that you would say, like. I know, I think that one that I read for cardiovascular diseases, Uric acid is a big one.

Uric acid is a very good one. So we've learned a lot about uric acid. Uric acid is a byproduct of purine metabolism. Okay. So also a byproduct of fructose metabolism. It's both. Okay. And, you know, if your uric acid's high, you don't know which one's a problem. But if you're eating a lot of meat and you're eating a lot of sugar. Okay. Probably. Probably you're not on the best diet.

Right.

Okay. So it's a sign of problematic diet, to be sure. Okay. Now, why is uric acid bad? Well, it's bad for two reasons. The first is it is the endogenous inhibitor of endothelial nitric oxide synthase, or enos. Now, this is the enzyme that lives in your arteries and keeps and makes nitric oxide. And nitric oxide is your endogenous vasodilator. It keeps your blood pressure down. It keeps blood flow moving. So when you have a lot of uric acid, your blood pressure goes up. And not only does it. Does that have its inherent problem of, you know, potential stroke, but it also means that organs aren't necessarily getting the blood flow and the oxygen that they need.

Problems are down the line.

Down the line. Okay, so that's the first problem with uric acid. The second problem with uric acid is it is also an inhibitor of an enzyme in the mitochondria called CPT1, carnitine pulmidowltransferase 1. Now, this is the enzyme that regenerates carnitine. And carnitine is the shuttle mechanism by which fatty acids get from the outside of the mitochondria to the inside of the mitochondria so that they can be beta oxidized, broken up into two carbon fragments, and burned to make ATP. So if you are poisoning your mitochondria with sugar, which interferes with amp kinase ACAD L&CPT1 through uric acid, and your uric acid's high, you know, that's pretty bad. So fasting insulin, uric acid, another biomarker that We've talked about last time, alt.

Right.

Alanine aminotransferase, which is a marker for fat in your liver. Now, the problem with that is interpreting the number exactly. So we talked about the fact that the upper limit for alt is really 25, and if you're African American, it's really 20. But the lab slip says 40.

It's because of the US average. Right.

Because the average has. Basically, the whole curve has shifted to the right.

Right.

So there are some very clear, easy biomarkers that could be used to look for disease before it even occurs.

So we're looking at fasting insulin, we're looking at uric acid, and we're looking at alt.

There are others.

Is AST one that you would be looking at?

Or AST tells you about acute mitochondrial dysfunction. Like if you drank, you know, a pint of bourbon, you know, your AST would go straight up before you even made the liver fat.

Right.

And also, you know, if you took Tylenol.

Right, right.

That's a great way to find liver. You know, damage due to, you know, various toxins.

Of course. Yes.

So AST is not as helpful, and it vacillates a lot more, so it's not quite as valuable. The other one that we think is very important is serum triglyceride. Fasting triglyceride, because that's telling you how your liver is processing carbohydrate. People think triglyceride is about the fat you eat. No, your LDL is about the fat you eat, the triglycerides, about the sugar you eat.

Right. And one thing that I find is that the liver is a very resilient organ. It's, you know, you can cause damage pretty quickly, and you can also turn it around pretty quickly.

Yeah, as long as it hasn't been damaged severely to the extent.

Right, exactly.

Once fibrosis starts, that never goes away.

So how does, you know, non alcoholic fatty liver disease progress into non alcoholic steatohepatitis or nash?

That's a great question. And I don't think the, you know, hepatologists who work on this even know yet. What I can say is that there's steatosis, which means fat in the liver, and then there's steatosis with inflammation. Now, what bridges that gap? How do you get the inflammation started? That's a complicated question. And, you know, we're working on it. You know, it may have to do with these liver transcription factors, because that's where all of the pharmacologic research has been directed is at LXR and fxr, but I'm not sure if that's really the answer. Here's what I know. I know that when we looked in the children that we took off sugar, we found that the percent liver fat was inversely proportional to the amount of choline in the liver. In other words, choline is a precursor to phosphatidylcholine, which is a precursor to being able to make triglyceride and export it out. So if you don't have enough choline in your liver and you get choline from a good diet, a nutritious diet, a high amino acid diet, because choline ultimately is, you know, is made from various sources that are, you know, replete. In an animal based diet, if you don't have enough choline, you can't export the fat out and therefore the fat builds up. And if you're not don't have enough choline, the chances are you also don't have enough glutathione and you don't have enough vitamin E and you don't have enough of anything else that makes the antioxidants that would actually suppress the reactive oxygen species, suppress the inflammation. So we have a clue that it's sugar plus bad diet. So you can have sugar plus good diet and have steatosis, or you can have sugar plus bad diet and have Nash.

Right, right. And you mentioned vitamin E, and I know that's something that my colleagues in pharmacy have been talking a little bit about. What's your take on vitamin E and non alcoholic fatty liver disease?

Well, so the problem with vitamin E is that it appears to have an inverted U shaped curve, that too little is not good for you, but too much is also not good for you.

Right.

And so finding the sweet spot in that inverted U is very difficult.

It's hard, yeah.

Studies of vitamin E repletion have not been valuable. They have not given us the answers we want. That's true. Having said that, vitamin E deficiency clearly appears to be associated with metabolic dysfunction.

Oh, interesting.

So you know how to, you know, utilize vitamin E. Vitamin E was one of the things in the Piven study that was done years ago in adult gastroenterology that basically helped fatty liver disease.

So if you're deficient as an antioxidant.

Yes. If you're deficient. Yes. Probably otherwise not as a supplement.

Right, okay, exactly. And those supplements, it can get dangerous with the fat soluble. You know, they kind of stick around. So that makes sense. So another thing that I wanted to ask you about and is Being talked about quite a bit, a little bit is Ozempic. And I know that. I'm sure you're getting a lot of questions on Ozempic, but what's your take? What do you think about.

So Dr. Casey means the Chief medical Officer of Levels Health, and I did a podcast, which I would refer everyone to just very recently, all about Ozempic and Wegovy and Manjaro, you know, the three, you know, GLP1 analogs. And so in I refer everyone to that. It's actually done quite well, and everyone should listen to it if they're interested in this subject. My take is it's better than nothing, but that doesn't make it good. And I think that's where we are. I think it will ultimately be an adjunct to other primary therapies as opposed to a standalone primary therapy by itself.

Right.

I think that it works because it tells your brain you've eaten. And so if you've eaten and then you try to eat more, you don't feel so good, you get nauseated, you get vomiting, you get diarrhea. Okay. And to some extent, that's aversive. And so you stay away from food, in part because it's aversive. Now, can that cause you to lose weight? Sure, 16% weight loss. I mean, that's pretty darn good, but, you know, at an expense, at a cost. And it turns out that a lot of patients end up with a lot of side effects, not just nausea and vomiting.

Yeah, a lot of people discontinue. I think they say, like, one third of people get off of it one third pretty quickly.

Pretty quickly. So one thing that has been shown is gastroparesis. Your stomach stops moving. Well, that's a great way to lose weight and make your life totally miserable.

Right.

And it doesn't go away when you stop the medicine. Oh, my God. All right. Another thing that's worrisome. It might be good, it might be bad, but, you know, I'm going to focus on the bad for a minute. Ozempic has now been used to try to treat alcohol addiction and food addiction and other addictions. And there might be a value to it, in part because that GLP1 analog, that information that binds at the nucleus tractor solitarius, that sends information to the reward center of the brain, to the ventral tegmental area. And so it's reducing dopamine and therefore reducing the desire to eat. Okay. Potentially reducing the desire to drink. Okay, that sounds good. Right? Well, it may reduce reward so much that it actually leads to depression and suicidal ideation. Now, we've seen this movie before. In 2006, there was a medicine that never got approved in the United States. It got approved in Europe, but never got approved here. That medicine was called Ramanabant, trade name Acomplia, was made by Sanofi and. And it had to be pulled from the European market after it had been approved. And the reason was because of multiple suicides. Because when you turn off the reward system, life's not worth living.

Right.

So will we find the same thing with Ozempic and Wegovy? I don't know. I don't know. But we've already seen multiple case series of patients who became severely depressed on these medicines. So these medicines are not for the squeamish. They are not to be taken lightly. Yes. Do they work? Yes. Do you lose weight? Yes. But where do you lose weight from? Turns out you lose equal amounts of fat and muscle. Now, losing fat is good. Losing muscle is not. If you lose equal amounts, that's not so good.

Especially as you get older.

Especially as you get older. Because sarcopenia, loss of muscle mass, is one of the hallmarks of aging and one of the things that increases mortality.

Right.

The goal is to keep your muscle mass up, not down. Again, ask any little old lady.

Right?

The point is, if you're losing both muscle and fat, are you doing yourself a service? So the jury, I think, is still out on these medicines. And I think because we didn't have anything that worked and now we have something that kind of works, everybody, you know, the pendulum has just swung.

Exactly.

And what ends up happening is that the pendulum ends up swinging into an equilibrium somewhere. And I think that will ultimately prove that, you know, these medicines will become an adjunct to therapy, but not a standalone primary therapy. That's. That's my prediction.

That makes sense. I mean, there's always a cost versus benefit, you know, ratio that you have to take into account. So always.

And, you know, with, with these medicines, you know, there is clearly a benefit, and I'm not discounting that. But the cost is much more significant than people are getting, giving, you know, paying attention to.

So you, you kind of mentioned the role of the reward center and mental health, you know, sugar and mental health. I know there's a huge correlation, but maybe you could expand on that.

We're gonna talk about it today.

Right? A little teaser for.

In fact, sugar and mental health, you know, are basically, you know, inversely opposite. Okay. People think sugar is reward. It is, but reward is not mental health. Reward is the opposite of mental health.

It's very temporary.

It's very, very temporary. And when the reward goes away, your brain is worse, you're worse off.

That makes sense. Well, excited to hear more about it today during your talk, there's another thing that I've been noticing. I know we've talked a little bit about this separately, but in the last couple of decades, there's been such a trend or a huge increase in prevalence of dietary restrictions and food allergies in the younger population. When you compare to older people, you don't see as much lactose intolerance, gluten intolerance. Why do you think that?

Well, that's a good question. And lots of people are researching that. My understanding, talking with many people in the field, it's all about the gut. You know, the gut is a sewer. Literally, it is a sewer, all right? It's a pipe, okay, With a lot of you know what running through it. And it is a sewer. Now, it has the capacity to extract good things out and keep the bad things in the sewer, right? Well, sometimes the bad things get out. There are three barriers in the intestine. A physical barrier called the mucin layer, A biochemical barrier called tight junctions. That's what goes wrong in celiac disease, and finally, an immunological barrier called Th17 cells, which make a cytokine called IL17. Now, when these three barriers are working properly, the bad guys stay in the sewer. But there are numerous things in our environment that will antagonize each of those three barriers. Examples. Emulsifiers. Emulsifiers are detergents. They hold fat and water together. Emulsifiers are throughout our ultra processed food supply. Food supply. Carboxymethylcellulose, polysorbate 80, carrageenan.

Prevalent in everything.

Prevalent in everything. Right. Well, what is an emulsifier? It's a detergent. What happens if you swallow detergent?

Not good.

It eats the mucin layer right off your intestinal epithelial cells. And now the bad guys get in. Number two, the biochemical barrier, the tight junctions. Now, it turns out those tight junctions require energy to be able to hold together. Like so if the cell ends up depleted of energy, they loosen, and bad stuff can get in between the cells because the tight junctions have failed. Now, they can go back because it's transient, so it's hard to see on a microscope. Okay? But when that fails, you can measure bacteria coming into your bloodstream. And it turns out one of the biggest drivers of that leak is sugar. And finally, the Th17 cells has been shown by several groups now that a high fat diet keeps that intact. But a high fat, high sugar diet causes the dissolution of all those TH17 cells. The IL17 is gone, and guess what? The bacteria take over. So sugar is bad at every one of those levels. Ultra processed food is bad at every one of those levels. And if you have a leaky gut, if you. If the stuff in the sewer ends up in your bloodstream, your immune system will say, wait a second, I'm under assault. I've got to make antibodies.

Right?

Okay. And then those antibodies could be against pieces of food, and now you've got a food allergy. Or it could be that those antibodies will, you know, be developed against a piece of food and will then use that epitope to find some other cell in your body that looks like it and attack it.

Inflammatory disease.

And now you've got autoimmune inflammatory disease.

Right, exactly.

So we think that most of the inflammation that is driving this phenomenon is coming from the gut because of our food.

So sugar is really the trigger to.

All of us, and sugar is the trigger.

Well, we're excited to hear more about the link between sugar and mental health. Thank you so much for your time.

And my pleasure, as always.

Thank you.

Sam.