Undoctrinate Yourself - #60 - Lipid Metabolism

Episode Date: October 25, 2026

This episode is lecture 39 from semester 1 of my course QuantumU. And on that topic: semester 2 of QuantumU is now enrolling! follow this link to learn more and enroll: https://dralexisjazmyn.thinkific.com/courses/qusemester2& if you sign up for semester 2 before Halloween, you'll get access to 7 bonus lectures from semester 1 (10+ hrs the subjects of biology and biochemistry).You can also join the full program to receive all of the lectures from semester 1 (40+ lectures on intro bio, gen chem, organic chem, and biochem) and semester 2 (which will be another ~20 lectures): https://dralexisjazmyn.thinkific.com/courses/quantumuCustom flexible payment plans available for all of my courses, email me at [e-mail] and we will get you set up.Enjoy the episode!

All right. Welcome to lecture 39, almost at the big 4-0, which is super exciting. And I think you guys are really, really going to like today's lecture. It's like the perfect blend of practical application and interesting science and, like, kind of nerdy stuff. So I'm excited to get into lipid metabolism today with y'all. And this is from chapter 17 of the book, roughly, though I'm not staying. sticking exactly to the sequence that the book is touching on and the book also goes into more detail on certain sections for sure. But I'm just hitting all of like the main points that I think you all should know in order to progress moving forward and be able to have a good

synthesis and understanding. Speaking of synthesis, the answers to the questions from last week. Number one, how many carbons does acetyl-CoA have? It has two carbons and we talked about specifically how when you have pyruvate, which has three carbons, going through PDH, pyruvate dehydrogenase to make acetyl-CoA, you're losing one carbon in the form of carbon dioxide. Of course, carbon dioxide has one carbon atom, two oxygens. So you're losing that carbon and two oxygens from the structure of pyruvate to make acetyl-CoA. Number two, what is the enzyme that allows carbons from pyruvate to enter the TCA cycle? That would be the one I just mentioned, PDH or pyruvate dehydrogenase, which is an enzyme complex, as we looked at last week.

Number three, name the three different types of reactions involved in the TCA cycle. Or name three different types. There's more than three. Three that you could have mentioned are redox reactions, which involved the movement of a hydride atom, which is when we're seeing NAD plus moving to NADH, for example. We also have dehydration reactions, which are reactions that are losing water from a molecule, and condensation reaction.

which involve two molecules coming together to form one. And like the biggest example of that would be oxaloacetate coming together with acetyt to make citrate in that first committed step of the TCA cycle. Number four, name three different metabolites that can be made from TCA intermediates. So these are going to be our cataplerotic reactions, reactions that are taking TCA intermediates away from the TCA cycle to make something else. So there's many, many examples, but three that I gave here are oxaloacetate can be used to make aspartate, the amino acid. Alpha ketagluterate can be used to make glutamate, the amino acid, and citrate can be funneled off

to make fatty acids. And there are many more examples, but those are just three. Number five, name three different metabolites that can make TCA intermediates. So these are going to be our anapleurotic reactions, the reactions that are making more, of our intermediates instead of pulling them away in the catapleurotic reactions. So again, many examples, but three here are propionate can be used to make succinyl co-A, glutamine can be used to make alpha-keta-gluterate, and pyruvate can be used to make oxalo acetate. And finally, number six, what are two negative regulators of the conversion of pyruvate to aceto-CoA? What are two positive

regulators. So two negative regulators of this conversion are ATP and acetylCoA itself. And this should make sense because you don't want to be unnecessarily funneling carbons from pyruvate into the TCA cycle if you already have enough ATP. You don't need to make more energy. And if you have enough acetylCoA, which is the direct product of this reaction. So both of those regulators are very kind of common sense that they will feed back inhibit the PDAH reaction in order to make sure that energy resources aren't being wasted. On the positive regulator side, two of the regulators you could have mentioned are AMP and NAD plus.

So AMP, when the levels of AMP go up, again, this is a sign within the cell that energy is in deficit and more energy in the form of ATP needs to be produced. Similarly with NAD plus, NAD plus, when that's higher, it's a sign of a lower energy charge within a cell. And so both high AMP and high NAD plus would be signs that the cell would benefit

from pushing more of those pyruvate carbons to aceto-CoA to support TCA cycle turning and thus support ATP production and NADH production, which ultimately leads to ATP production, so very related. Okay. So before we zoom in on lipid metabolism specifically, I want to just briefly highlight the rule. role of the liver in the body. I think a lot of people have general ideas of what the liver does.

I feel like the biggest kind of common knowledge concept that people have an idea of is that the liver is important for detoxification. And it is. And we're certainly going to cover that at some point before we finish up our biochem lectures. I have to think about where it fits in best. But there are these enzymes called cytocrone P-450 enzymes that are playing very important roles in the different phases of detoxification within hepatocytes within the liver, which is the main organ that participates in this kind of xenobiotic metabolism. And when I say xenobiotic metabolism,

I'm referring to molecules that the body's not making, that the body is encountering through food, through the environment that are absorbing into the body. Some of them can be toxins. Though, of course, the dose kind of makes the poison. So something at a lot. lower level may not be poisonous versus when that dose gets moderate or high. Now suddenly there can be noxious effects, but essentially the cytochrome P450 system is responsible for making sure that certain molecules are selectively eliminated from the body. My partner Keith, who works at Merck, he works in pharmacodynamics and pharmacokinetics, and he does these sip screenings all the time, where basically when you're in the drug development pipeline and you're developing a new drug,

all these drugs, for the most part, are being metabolized by the cytochrome P450 system. And so they are a major root of clearance, of drug clearance within the body. And when you're developing a drug, and this doesn't even necessarily need to be a drug, you can also do these same types of studies for plant alkaloids, like different active constituents within herbs, things like this, that you're curious about how the body is metabolizing them. and when we want to understand like an effective dose of something, and this was actually the end of my PhD as well,

I was doing some studies on the pharmacokinetics of endogenous metabolites. So pharmacokinetics, or P-K, is essentially looking at the rate of appearance. So how long does it take the drug or molecule to be absorbed and reach into the blood? Then what dose, what is the maximum dose or concentration, rather, that it reaches in the blood given a specific dose that was provided? and then how long does it stay at that concentration in the blood, how rapidly is it eliminated from the system? And elimination is kind of vague,

because if we're just looking in the blood, we don't necessarily know if that molecule is being metabolized into something we're not measuring, if it's being absorbed by the fat tissue or another organ, or if it's being converted into a metabolite and then excreted via the urine or the feces, for example, all we might see that it is disappearing from the blood, but that's not necessarily telling us where it's going per se.

So the cytochrome P450 system in the liver is one of the major roots of elimination and that it helps to essentially make molecules more water soluble so that they can be excreted in the urine, or in some cases make it more fat soluble to excrete it via the bile, which then gets lost in feces. So the liver is playing very, very important roles in terms of detoxification.

And like I said, we'll get into the technical details of that in a different lecture. But in addition to those roles, which I feel like people generally have a sense of, though not the specifics, the liver is also the primary metabolic hub for the entire body. It is coordinating signals from the environment, from the larger organism as a whole, and integrating those signals to understand the general energy charge of the system. And it's listening, it's got in the same way that we have eyes, and ears and a nose and taste buds and a sense of touch. At the cellular level, you can think about these senses being expressed as receptors.

So if a cell has a receptor for glucagon or insulin or testosterone or whatever it is, whatever the molecule or like factor or hormone that we're thinking of is, if there's no receptor there on that cell to bind to that hormone to elicit that cascade or take up that factor and allow it to exert its effects inside the cell, that it's as if the cell doesn't, it can't see it, it can't feel it, it can't hear it, it's like it almost doesn't exist. In the same way that if you, I don't know, plug your ears, and then there's a song playing in the room,

to you, it's as if nothing is happening because you can't actually hear it. That stimulus isn't coming into your system and eliciting a response. So the liver is full of eyes, ears, smell, taste, touch for many different factors in the body, many of which are hormones, including insulin, glucagon, sex hormones, as I was just mentioning. And these hormones in particular are critical for providing the liver with information, again, about the energy charge of the system. So when insulin goes up and insulin binds to the insulin receptor on the surface of a liver cell,

it is telling the liver that there is an abundance of car. carbohydrate energy available, that there's an abundance of energy available in general. And what does that mean? That signals to the liver, okay, we have an abundance of carbohydrates of energy available. That means I can store some of this carbohydrate for later in case I can't find more carbohydrates or more food tomorrow. Let me store some of those carbs as glycogen, and let me shut off gluconeogenesis because making glucose from scratch, again, is a very expensive process. And you don't want to be making glucose if there's plenty of glucose coming in, which again is being signaled by elevated insulin levels. And so that insulin signal provides the liver with

the information it needs to know to turn the volume down on some pathways and turn the volume up on other pathways. Some other things that get turned up would be like fat synthesis, cholesterol synthesis, glycogen synthesis, the things that are getting turned down, beta-oxygen Cetone body synthesis, gluconeogenesis, these are all being turned down in that fed state, which again is being signaled by insulin in this case. In contrast, the factor that opposes insulin, it's like on the teeter-totter here, we have insulin on one side and we have glucagon on the other side. So insulin is being produced by the pancreatic beta cells.

Glucogon is being produced by the pancreatic alpha cells. So when insulin goes up, glucagon goes down, and as insulin goes back down, glucagon begins to rise. Glucagon is the signal to the liver or the muscle, the fat, etc. That energy is in decline. Energy availability is becoming more scarce. What does that do? When glucagon binds to that glucagon receptor on the liver cells, it tells the liver, hey, we're kind of in a state of energetic scarcity. That means can you please liberate some of that

stored glucose from your glycogen to help maintain blood sugar levels? Can you please turn up the knob on gluconeogenesis to make sure that we're maintaining those steady glucose levels in the bloodstream, even despite no food or carbohydrates being available? Can you turn up fatty acid beta oxidation and ketone synthesis because we're going to need to compensate for some of the lack of glucose and carbs coming in through the diet. These are all intelligent responses from the liver cells to this signal of scarcity. We can kind of think of as insulin kind of being this signal of abundance and glucagon being the signal of scarcity from an energetic, like a bio-energetic perspective. So the liver is the one coordinating all this for the entire rest of the body. If the liver wasn't

doing its job, the brain would run out of glucose. And if there weren't ketones that were also being produced by the liver, which we're going to talk about today, you know, the brain would be dead very, very quickly because the brain requires glucose at all times. That glucose requirement can be tamped down in the context of long-term carbohydrate restriction, but there is always still a very basal level of glucose required in order for neurons to function. And I may have mentioned this before. When we looked at glycolysis, I showed you that some of the glycolytic intermediates in the payoff phase of glycolysis can get siphoned off to make glycine and serene. These are two amino acids, but not only are the amino acids, they're also important neurotransmitters.

Glycine in particular, and I believe I mentioned this, is one of the primary inhibitory neurotransmitters in neurons. So it's playing a very important role in regulating neuronal activity. And so if there's no glucose available at all for the brain, now it can't make its own glycine. Worth noting, the blood-brain barrier does not permit non-essential amino acids from traversing through it. So the brain needs to make all of the non-essential amino acids that it needs itself. And this is very advantageous because, again, the non-essential amino acids, a few of them serve very important roles as neurotransmitters. Glutamate is the primary excitatory neurotransmitter and glycine is the primary inhibitory neurotransmitter. If the brain could just willy-nilly take up glycine and glutamate from the bloodstream,

which are constantly circulating and being made by a whole host of tissues and exchanged in the bloodstream, it would completely disregulate central nervous system activity. As a way around this, the brain has closed its doors to non-essential amino acids in general, including glutamine, glutamate, and glycine. But it does allow the essential amino acids through. Well, it turns out essential amino acids like phenylalanine and tryptophan play very important roles as precursors to other neurotransmitters, including dopamine and serotonin. So the reason that that works is because it takes multiple steps of conversion in order for the tryptophan and the phenylalanine to be converted into dopamine and serotonin. And so the brain can instead of just blocking these amino acids from coming in, instead,

the brain can just simply regulate the steps that synthesize the neurotransmitters from the amino acids. And so because there's multiple points of potential regulation, that prevents there from being a catastrophic issue when you eat a steak, because now you're getting a bolus of phenolamine, tryptophan, and other amino acids, but it's not actually sending your brain into full chaos and heat death because the brain is very good at regulating the flux through these neurotransmitters, synthesis pathways. Anyway, I digress a bit, but it's very important to understand because the availability of certain substrates, whether it's glucose, ketone bodies, amino acids,

is highly, highly coordinated by the liver. And so I mentioned that glucose can be pushed down quite low. And these were the studies from George Cahill back in Harvard in the 60s, I believe. It could have been the 50s maybe. Back when it was the Wild West of science, he took a few obese individuals and he fasted them for, I believe, it was 12 weeks straight, maybe it was eight weeks. I think it was like just over 40 days of fasting, like no food at all. And then at the end of that period of time, when they were extremely fat-adapted and extremely ketotic, he then took insulin and he pushed it into their bloodstream to see how low he could get glucose levels before they started to have seizures.

Absolutely just like would never pass any sort of, you know, regulatory bodies and institutions today. But again, it was the Wild West back then. And he found that typically blood sugar levels in humans are sitting around 5 millimolar. And he, in these extremely ketotic, fat-adapted, fasted individuals, was able to push glucose levels down to around 2-millimeter without any, seemingly any side effects at all. So that tells us that you can cut glucose levels by a little more than half in the bloodstream

and assuming that person is very keto adapted, which would be in this case, they actually are fine with regards to their central nervous system function. And this is because ketones can largely compensate for a lack of glucose in the brain, in the neurons. So when there's not enough glucose available, the ketone bodies can kind of swoop and take a lot of the load off of carbohydrate metabolism to support energy production, ATP production. And actually, on a per-carbon basis, ketones are a better fuel source than glucose is for neurons and in general.

And what I mean by that, it's like burning high-octane fuel versus ethanol. It's like you want to put the best fuel in the race car, right? So it turns out the more efficient, cleaner burning fuel, so to speak, speak, is actually ketones. But again, we still always need some of that glucose to support the synthesis of our non-essential amino acids in the brain, like serine and glycine and glutamate. Okay. What else do I want to say there? There was something else I was going to say. Liver is a metabolic hub. Glucose regulation, fat regulation, ketone production.

Something about ketones. We're going to be talking about ketones later today, too, so maybe it'll come back to me. Yeah, maybe it'll come back to me. It doesn't matter. But anyway, here's just a bit of a schematic here that's showing us what the liver is essentially up to. So the liver, this is in a fasted state, in a fasted state, and we're going to look at what's going on in different tissues a little bit later. in adipose tissue, when glucagon binds to the surface of these fat cells, it triggers lipolysis. What is lipolysis? Fatty acid breakdown, or essentially, not exactly fatty acid

breakdown. Triglyceride break down into fatty acids. So we're going to talk about what that means a little bit when we talk about different lipids and their structures. But essentially, suffice to say for now, the triglycerides are broken down into free fatty acids and glycerol. So the backbone of a triglyceride is glycerol. That glycerol can go into the bloodstream. Those fatty acids also go into the bloodstream. They bind to albumin, which is the primary serum protein within your blood that serves as a kind of shuttle bus for anything that's more lipid soluble. So our fatty acids, our steroid hormones, for example, any sort of lipid soluble drugs or molecules that are coming in through the diet would also be kind of found there. But the glycerol in particular is really important

because it serves as a major substrate for gluconeogenesis. So the fat can go on to provide an energy substrate for a variety of different tissues. And the glycerol can go to the liver and be used to make glucose de novo from scratch via gluconeogenesis. Worth noting is that fats cannot be directly oxidized by the brain. There is very little fatty acid transport from the blood in to the brain. There are some exceptions with the exceptions of like some of the essential fatty acids like DHA. There was a DHA transporter that was characterized a few years back.

So certain fats are permitted through the blood-brain barrier, but they're not there to be oxidized. Instead, the brain, again, burns ketone bodies, which are kind of an artifact of accelerated fat metabolism in the liver, which again, we're going to talk about later. the liver can take fatty acids to make ketones, which can then go on to feed the brain and the muscle and the heart as well. And then fatty acids liberated from the fat tissue can also go on to directly support a variety of different tissues in the body outside of the brain. So the muscle, the heart, all of the visceral organs, etc. So this is just kind of a very basic overview of metabolic exchange in fasted state mammals, let's say.

And this was actually the main focus of my research at Princeton. And we're going to double click on that later because I'm finally going to be able to walk you all through my paper because I think we've actually learned enough to be able to understand it now, which is great. But anyway, let's move on for now. Okay. So, whoops, lipid digestion and assimilation.

So you eat fat. It's coming in through the day. diet. You eat, I don't know, a nice fatty ribby or an avocado or salmon, whatever it is. There's fats coming in through the diet. You chew up that food. The first stop in the mouth, digestion-wise, it's really breaking up the food into small particulate matter, emulsifying it with, well, kind of making an amalgam with saliva. The saliva's role is really to help kickstart carbohydrate metabolism in the mouth. Saliva contains amylase, which helps to begin breaking down carbohydrate molecules in the food into our smaller sugar units. So the full purpose really of chewing and saliva

production is starting the digestion process by pre-processing the food into smaller pieces and also beginning to break down carbohydrates. You swallow the food. Now it's entering into your stomach where you now have protein digestion beginning to start. So you have HCL, the hydrochloric acid produced by the parietal cells in your stomach. It's being secreted. It's creating a low pH environment, which is required for the activation of some of the peptidases, so the protein digesting enzymes that are produced and secreted and allowing the stomach to begin protein digestion in particular. But in addition to our peptidases, not only do we have those protein digesting enzymes, but we also have things like light paces as well, which begin to kind of chop up the triglycerides coming in through the diet into free fatty acids. Though typically not all three get cleaved off, I believe it's typically only two.

And then one of the fats stays on the glycerol backbone and it gets reformed in a minute, which I'm going to talk about. So essentially, not only do we have enzymes that are beginning to work on the fats, but we also, maybe even most importantly, to a certain extent, have bile as well. So bile produced by the gallbladder, one of its main roles is to help facilitate the emulsification of fat coming in through the diet. What does that mean? In the same way that when you make salad dressing, if you just put oil and vinegar in a bottle and shake it up, They stay as two layers. But now if you add mustard or honey and then you shake it up,

it stays as this nice thick dressing. Same thing with like mayonnaise. So these are all examples of emulsions, and an emulsion is essentially a suspension of super tiny lipid droplets. But when we break down lipids into tiny, tiny lipid droplets and create this suspension, this emulsion, it's increasing the surface area available on those lipid droplets. for different enzymes to act or the different machinery in the small intestine to act upon

when it's packaging up these fats. So the bile is very, very important for that process, not only for fat digestion and assimilation, but also for fat soluble vitamin assimilation as well. And of course, this is why people who get their gallbladder removed are told they need to eat a low-fat diet, essentially. But it's not only, you know, fat deficiency, that can happen from not having a gallbladder,

but also fat-soluble vitamin deficiencies as well. Worth noting that when the gallbladder is removed, there is still bile being produced by the liver, but it is a constant trickle into the gut instead of having this kind of bolus that's released upon consumption of food and fat, which is actually a problem because bile is an emulsifier, as I just mentioned, in the same way that like mustard or honey can serve as an emulsifier or soy lesothin. Emulsifier is something that can bind to something water soluble and something fat soluble at the same time and hold them together.

And we looked at this back in our chemistry lectures. We talked about amphiphilic or amphipathic molecules, which are also what's present in soaps. So this is the same concept, emulsification as it relates to soaps. The reason that you use soap on a greasy dish in the sink, and it allows that grease to be taken off the dinner plate, is because the soap is able to bind to the grease and the water simultaneously, thus allowing that grease to be stripped off of the dirty dish. So the problem with not having a gallbladder is that you're getting this constant trickle of bile

into the gastric compartment. and what that's doing is it can actually begin to emulsify or break down the barrier, the gut barrier. And so, obviously, you know, nature doesn't make mistakes. The gallbladder is a very important organ and absolutely makes me sick how quick surgeons and doctors in general are to recommend getting gallbladder removed with, you know, abdominal pain. And obviously there may be some circumstances where it has to come out. if there's like giant stones that can't be broken up or, you know, dealt with. But I have an example of a good friend of mine who when she was like 13 years old had abdominal pain.

The doctor told her she needed to get her gallbladder out. She got it taken out and the abdominal pain didn't go away. It wasn't actually the gallbladder causing the pain. And there are no superfluous organs, right? All of these organs play very important roles in the body in general. The whole idea of a vestigal organ is also, a total misnomer and like a fallacy. For example, the appendix, we know the appendix plays very important roles in helping to reseed the gut microbiome, especially after infection or antibiotics.

So the idea that it's just, you know, a vestige of our past and it was only when we were eating raw meat that we needed that is absolutely nonsense. It's actually, it does play very important roles in making sure that the gut microbiome populations are being maintained and diversified, etc. And that's not to mention, of course, the entire GI tract and the gut associated lymphoid tissue plays critical roles in whole body detoxification, fluid balance, and nutrient transport, as you will learn in a moment. So let me get into that.

Once those fats are emulsified and we're now moving into the small intestine, let me check the chat really quick. Medical community is very set in their ways, totally. And it's based on like a nonsense. It's based on pseudoscience in a lot of cases. It's just simply dogma without even the evidence to back up the recommendation. And I was just talking about this with somebody yesterday, especially in the realm of psychiatric care.

Half the drugs, they don't even have a mechanism of action for how they work. It's literally just like experimentation, kind of, um, it's like treating patient. as guinea pigs, and that's also why in psychiatric care, they're often giving multiple drugs and having you try out different things to see what might work with your individual body or chemistry or whatever, but they're literally just throwing stuff at the wall and seeing what sticks. There's no logic or first principles behind what they're doing,

and if there was, then they would actually be having to look at, okay, what environmental inputs are potentially influencing the way you're feeling, the way your brain is processing information, et cetera. And of course, when you go that route, there's no money in giving specific kind of lifestyle and dietary recommendations that could be absolutely life-changing for somebody, but it doesn't help meet the bottom line and status quo with regards to like the capitalistic inputs. Courtney said, yes, I'm only tested for a duration of six to eight weeks. Totally, totally. Yes, incentives dictate outcomes, exactly. Yep. Okay. So, we're now in the small intestine. We've emulsified.

our fats. We began chopping them up with lipaces. Now it's time for these fats to be packaged and sent off to the rest of the body. So we're going to look at like what these structures look like in a minute, but essentially the small intestine cells take up this fat and inside the cells, they package them into something called a chylomicron. So a chylomicron is like a big old school bus for fat and cholesterol and fat soluble vitamins. Now, the chylomicron is built. Everything is stored inside of it. It's this big vesicle, so it's a membrane-bound kind of bubble full of fat and cholesterol,

fat soluble vitamins, phospholipids, etc. And once it's packaged and it's filled up, it gets shipped off, but it doesn't go into the bloodstream. Instead, it's actually dumped into the lymphatic system directly, which then ultimately ends up mixing with the bloodstream a bit upstream. But the lymphatic system is absolutely critical for fat mobilization after the digestive process mobilizing those chylomicrons to get where they need to go, whether that is to dump all fat to be oxidized or if that's to dump all fat to be stored within adipose tissue.

And so we are going to look at that in a minute. I can't remember exactly that's on the next slide. But first we're going to talk about different types of lipids, just for clarity. Doctors never mentioned lymphatic drainage. Totally. Totally. They act like the lymphatic system doesn't exist.

It is absolutely insane. And especially when you learn about the lymphatic system and you learn about all of this lymphatic tissue that's around the breasts, and then women are wearing these constricting bras like all day, every day. and you wonder why you develop cis and polyps and you know all of these issues around the chest area and the lymphatic system in general

like we're literally blocking the flow of fluid and nutrients and waste for detoxification in any part of the body that's going to be a problem but you especially don't want that around you know your chest area because it's kind of a hub between the lower and upper body's lymphatic exchange

so it's just it's so crazy to me like as soon as you start learning about the actual structures behind these different systems, it becomes so clear why so many of the things that we're doing and that we think are normal are just completely pathologic. Okay, so let's double click a little bit on different types of lipids, just so we're clear on terminology moving forward. So a fatty acid is, we talked about this before, but just as a refresher. we have a long fatty acal tail so an acal group is just something that's like a long

hydrocarbon so as we learned in organic chemistry whenever we have this kind of structure here we're showing a carbon chain we're just not writing the c and h atoms but for example this little peak here is a carbon atom bound to two hydrogens because carbon can only have four bonds so there's two bonds to other carbon atoms and then there's going to be two implied hydrogen here. And then at the end of the saturated or the end of the fatty acid, we have a carboxylic acid group. That's what makes the fatty acid a fatty acid, the carboxylic acid group. This is a saturated fatty acid because it has no double bonds in the structure. That's what differentiates a saturated fat from an unsaturated fat. In contrast, let's look

at a polyunsaturated fat. So a polyunsaturated fat is a fatty acid that has a fatty acid that has more than one double bond in it. A mono-unsaturated fat would be a fatty acid that has one singular double bond in its fatty chain. So we can see here, this is DHA. So we have one, two, three, four, five, six double bonds in the structure. And this is considered an omega-3 fatty acid, whoops, because the last double bond is on carbon one, two, three. So this is three. So this is three. from the end of that fatty chain, there is a double bond. So that's why it's called omega-3. Omega-6 would be as if we went,

one, two, three, four, five, six. So if there was no double bond here and only this one was there, that would be an omega-6 fatty acid. Okay, one thing I just want you to compare visually right now is if we look at the saturated fat compared to the polyunsaturated fat, what is the difference here?

obviously we have the double bonds, but what's the implications of that? We can look and see here that every time we have a double bond, it's creating a change in the structure of that chain. So whereas the saturated fat has this long, straight chain, the polyunsaturated fat is like this winding road, right? Why does that matter? I described this way back in some of the earlier lectures, but just as a refresher, this has huge implications with regards

to melting temperature. So basically whether something is a liquid or a solid at room temperature. So the reason that saturated fats have a high melting temperature, meaning that butter is solid at room temp, even more so, beef tallow is solid at room temp. The reason being that when you have a bunch of saturated fat like stearic acid, which is legitimately very, very enriched within beef tallow, the chains, this long fatty chain,

they can stack on top of each other really nicely. So let me get my pen if I can. So that means we have a bunch of these molecules and they're all stacking super nice on top of one another. Above, below, et cetera. Why does that matter? Because they stack so nicely on top of each other geometrically, the intermolecular forces between molecules are strong.

And so what does that mean? It means it takes more energy to overcome the strength of those interactions in order to separate the molecules and melt the fat. In contrast, when we have fats like DHA, these molecules, imagine having two DHA molecules next to each other, they can't really associate very easily with one another

in that same way that we get with the saturated fat. So that means they don't really have super strong interactions between the molecules. What that means is that even, room temperature, you're going to have a liquid already. So this is why canola oil, soy oil, vegetable oils, et cetera, they're all liquid at room temperature because it's already melted. And even if you put canola oil in the fridge, it's still not reaching its temperature where it becomes a solid versus something like olive oil, which is a mix of saturated and mono unsaturated fats.

If you take olive oil and put it in the fridge, it does indeed solidify. So all of this, melting temp. This is all reflective of the strength of the intermolecular forces between the fats in the fat source that you're looking at, whether it's beef tallow, olive oil, canola oil, butter, tallow, et cetera. So kind of cool, a little bit nerdy, but also super interesting in my opinion. And there are pretty big implications to that as well. Oh, by the way, the reason that fats like DHA and the omega-6 fats and the omega-6 fats and the omega-6 fats and the omega- honestly are very easily oxidized because each point of unsaturation, every time you get a double bond, it makes it more easy for electrons to get stripped off of the molecule. And when you oxidize a fat,

it becomes reactive and inflammatory, frankly. Because it's looking to kind of strip those electrons back from somewhere else. And so this is why it's really important to, you know, not eat seed oils because they're industrially processed. I mean, obviously, there are exceptions. Like, if you get a good, cold-press black seed oil or a good-cold-press sunflower seat oil, that could actually be beneficial.

But if we're talking about our industrially produced monocrop oils, these hyper-ultra-processed oils, they're going through the absolute ringer, and they end up having to be deodorized by the end because they smell so rancid that nobody would ever use them if it wasn't for that deodorization process.

So when you eat these rancid oxidized oils, it foments an inflammatory response in the body. It's not good. And this fat is being used to make new cell membranes, for example, and especially the rapidly turning over tissues. So we don't want to be making our cell membranes out of really crappy fat. This is also why it's very important to get enough omega-3s, yes, but the sourcing is absolutely critical. So most fish oils available on the market are coming to the consumer rancid.

so you're not actually getting the benefits you think you're getting from a fish oil if it is rancid. This is also why it's, you know, great to be able to eat your omega-3s whenever that is possible because the whole food is helping to stabilize those fats in their correct form and electronic status because they're surrounded by a whole milieu of, you know, other biomolecules, etc., that helps to keep it stable versus an isolated fat within a pill or a capsule or a liquid, it's much more vulnerable to breaking down. So I think that's all I want to say there for the most part. We already kind of touched on this previously, just that although using an algal oil is way better

than not getting enough DHA at all, the algal oils are not going to be as bioavailable as eating EPA and DHA from animal-based sources because of the position on the backbone of the triglyceride. So what do I mean by that? Let me just briefly fast forward to this slide. So focus over here on the right. We're going to circle back to the left later. A triglyceride is the stored form of fat. By far when you're consuming fats from animal foods, you're getting it in the triglyceride form. The plant forms as well. Like if you're eating. an avocado. It's going to largely be in the triglyceride form where we have three fatty chains, so three fatty acids bound to a glycerol backbone. This is what I showed you all earlier as well.

When lipolisis happens, these fat molecules get cleaved off the backbone. The glycerol backbone can go into the bloodstream, then go to the liver where it is used to make glucose from scratch, and the fats can be burned with beta oxidation. So these positions on the, you know, the glycerol backbone have names. So this would be considered as S-N-1. The second one is, oh god, S-N-2. And this bottom one, lastly, is S-N-3. This is just a naming convention to be able to differentiate between the different carbons on the glycerol backbone. Now, it turns out that when you have a fat bound in this SN2 position, it is more bioavailable at the level of absorption of the fats within the GI tract, within the small intestine,

like we talked about a little earlier. Just the mechanism by which the fats are reconstructed after being predigested, let's say, in the stomach. This SN2 fat is the most likely to be retained and then ultimately make it into the body. So it turns out that animal-based sources of EPA and D-HA are enriched in this SN2 EPA and D-HA and D-enriched in SN-1 and SN3 versus something like an algal oil is typically enriched in SN-1 and SN3. So you may essentially not have as high of a bioavailability of omega-3s within an algal oil

compared to an animal-based source. Now, again, it's still way better to get it in at all. so if for whatever reason you can't do seafood and you can do an algal oil, I would still say, you know, go for it. You're still going to be getting a decent amount of that in, so it's way better than nothing. But we really need to be getting DHA in directly as we talked about, gosh, when did we talk about this?

Now I'm actually trying to think if we did cover this directly. So what I was going to say is plant-based sources of omega-3, so omega-3-A-LA, is very very very. very, very poorly converted into EPA and DHA. So only between 5 and 10% of ALA consumed can reach to EPA, and only 0.5 to 5% can ever reach to DHA. So if you're only relying on ALA from walnuts or flax seeds, for example, in order to get your omega-3s,

you are going to be woefully, woefully starved of DHA and EPA. being the most important, the longest chain, and having the most implications with regards to eye health, brain health, and inflammatory status in general. That's made even worse by the fact that I have a schematic for this somewhere, and I'm trying to remember maybe if I taught this in MPB, and that's why I'm like having a false memory that we discussed it. But essentially, if you look at the pathway by which the body uses to elongate ALA, which again is from like flaxseeds, walnuts, alpha-inolate acid, into EPA and DHA, that same machinery, those enzymes are being used to process omega-6 fats into

longer chain fats as well. So if you're only consuming ALA, and on top of that, you're also eating a bunch of these processed seed oils that are very enriched in omega-6 linoleic acid, not only are you barely going to be making enough DHA with the ALA alone, but also now those enzymes are going to be tied up processing the omega-6 fats, and they won't even be as readily available to help elongate that ALA into EPA and DHA, so you're going to be far more on that low end of the range, like 5% conversion to EPA, 0.5% conversion to DHA. So the bottom line is there. We really need to be getting DHA directly into the body.

Again, Caviar is my favorite, favorite way of doing that, just because it is so bioavailable. it's in a different form. So that brings me back to what we're actively discussing, which is the different lipids. So this is a phospholipid. Phospholipids have a phosphate group bound to them, and the phospholipid form of EPA and DHA and any fat in general, but specifically with the omega-3, it's important,

to know that these phospholipid forms are highly, highly bioavailable. in particular in the eyes and the brain. So in particular, if you're looking to support eye health, brain health, lowering brain inflammation, supporting brain function at the biophysical level, eating caviar is like the best thing you can do in those contexts. So anybody who actively has neurodegeneration or wants to like, you know, avoid neurodegeneration, especially if it kind of quote unquote runs in your family, for example, or you experience a lot of brain fog,

or you had any sort of hand injury, concussion, CTE, any of this, like all of these people need to be caviar maxing for sure. And if you're just looking to support cognitive performance in general, or maybe you've had some issues with your eyes in the past, the eyes also absolutely require high levels of DHA. And so making sure that we're getting enough, especially in that phospholipid form, are going to be imperative. Can I provide brand recommendations?

Yeah, so the two brands, that I typically buy one. So I typically get sturgeon row, which is kind of like the bougiest caviar you can get. You can also totally get salmon row. If you can stomach it, I know some people will freeze it and then put it in a capsule and then just take it that way. Or you can just put some in your mouth,

hold your nose and put it down the hatch. Salmon Row is going to be full of EPA and DHA, so no worries there. It just tastes really bad. And I'm very Venusian and I want to enjoy what I'm putting in my mouth. And so I get the expensive ones. So Fishwife. is one brand. They make sturgeon caviar. They have a couple different tiers. So depending on

how boogey you want to go, you could be spending like $100 for an ounce and a half or something. Or you could be spending like 60 bucks for an ounce and a half. The other brand is called Caviar Roos, R U SSE. And they also have multiple different tiers. So those are the two that I typically you get. There is a new brand, I think, out of New York City called Cavie, so C-A-V-I. And I think they actually have a subscription service where they mail you your caviar, like however often you want. And they're bigger tins as well. So I actually am about to get on that train and give them a try. It seems like they're pretty good, though, from what I hear. So those would be some options. Okay, let me, I will let you know. Okay. So that's the phospholipy.

We talked about fatty acids, saturated versus unsaturated. I just mentioned the phospholipids. We're going to double click on phospholipids again on the next slide because they're very important with regards to the structures of our cells. And then we have our triglycerides, which I just showed you on the next slide as well, just the basic storage form of fat, glycerol backbone, with three fats coming off of it.

And then the last one we're mentioning here are sterols, with cholesterol being the most important sterol within human biology. And cholesterol is absolutely critical, not only from a structural standpoint, but also as a major precursor for all the steroid hormones, including cortisol, or corticosteroids, aldosterone, progestrone, testosterone, estrone, estrogel, estrogens, essentially. So all of these hormones are made directly from cholesterol as well. And then there are some more, obscure fats that are nevertheless very important. So these would be our sphingolypids. So sphingolipids are important structurally as well as in regards to cell signaling. So sphingomilinilin and cerebrosides.

So that's these two here. We have sphingomilin and cerebricides. They're both very important constituents of the myelin sheath that protects the central nervous system nerves. and basically acts as an insulator. And of course, the myelin sheath is what is being attacked in the autoimmune disease, multiple sclerosis, MS. So that myelin sheath is required to insulate the electrical impulse from being able to kind of scatter around and kind of bleed off into the surrounding environment. And that's also why people with MS, they can get these like brain zaps and this feeling of like,

not quite a seizure, but it's a feeling of like the electricity essentially escaping from where, it's supposed to be into the surrounding tissue. So those are the sphingomyelin and cerebricides, and then our glycosphynolipids are important for facilitating cell-to-cell adhesion, tissue formation, and also immune recognition. So these can be often on the surface of cells, signaling into the environment,

about allowing essentially the immune system to get a sense of what's going on within that cell. cell. So there's a lot of these kind of modified lipids that are involved in immune cascades and immune sensing. And we will talk about that way more extensively when we get to our intro to immunology lecture series in semester two. Let's double click on our phospholipids for a second. So here's the structure of a phosphatidylcoline, PC. You may have heard of it because I know there's this body bio company that like thinks that the sun rises and sets on phosphatidylcholine and don't get me wrong it's very very important i don't know how relevant it is to take it in isolation though um we're

really meant to kind of receive it in the context of food um but nevertheless this is what the structure looks like so we see we have a phosphate group here we also have this positively charged nitrogen group hanging out and then we have these three fat chains coming off of that backbone Sorry, two fat chains. This is a separate. This is just a fatty acid, staryc acid. So nitrant group, phosphate group, and two fat chains coming off of the backbone. So this is what it looks like in the space fill model, kind of like a rendering. And when you look at that in the context of a membrane, our phospholipids are absolutely critical for cell membranes. So the actual structure of the cell membranes, as well as all of our vesicles that are produced from cells or within cells as well.

So an example would be like exosomes, which I think people talked a lot about quite a few years ago. But a lot of these little vesicles, but cells in general have this phospholipid layer. So you can also have a my cell, which looks similar. So in the my cell, we're just taking a fatty acid molecule that has this polar, head group, which is the carbonylic acid group, and then the fat tail points in, and it can come together to form this my cell where all of the carboxylic acid head groups are pointing out, and all of the fatty tails are pointing in, and this could be also like a situation for these kind of tiny vesicles within cells versus the cell membrane itself is made by, with a lipid bilayer,

meaning we have not one, but two layers of phospholipids. The top ones are pointing down, the bottom ones are pointing up, and this serves as the boundary between the cell and the extracellular environment. So that lipid bilayer forms the cell membrane, which is also what regulates, what can come in, and what can leave a cell as well. So depending on what fats are composing these tail groups, it dictates how much fluidity the membrane has, how rigid versus how fluid it is. And that's actually highly relevant, too, because the membrane dynamics is like a whole field of

biophysics that kind of is teaching about how the fat composition and the fluidity dictates essentially how the cell functions at a very fundamental level, which is all super interesting stuff. Yes, eggs are a good source of choline in particular. I'm sure there's some phosphatidyl-cold as well. But yes, coline, which would be like that backbone structure, is definitely enriched within eggs. Absolutely. Okay. So let's look a little bit now at cholesterol. So cholesterol being our most important sterol produced in the body. This is the cholesterol synthetic pathway. You can see there's many, many, many, many, many, many steps involved in it. So note that the starting material for cholesterol synthesis is none other than

acetyl-CoA. The same input into the TCA cycle, right? So you can use it to make energy, but you can also use it to make cholesterol as well as fat too, which we'll talk about in a little bit. You don't need to know all these steps in any, you know, by any stretch of the imagination. but just know that there's many steps. And the more steps are on a pathway, typically the more regulated that pathway is,

and also the more multi-purpose that can be. So in some cases, when we have a lot of steps like this, it means some of these intermediates can be siphoned off and used for other things. For example, the 70 hydrocholesterol is the precursor to pre-vitamin D in the skin. So you might remember that UVB light is required to make pre-vitamin D

because what happens, when UVB light strikes the 70 hydrocholesterol molecules in the skin, it creates a non-enzymatic reaction that directly converts 70 hydrocholesterol into pre-vitamine D, which can then be converted into vitamin D3, which can then be converted into 25 hydroxy vitamin D in the liver, and then ultimately into 1 25 hydroxy vitamin D in the kidneys, which is the final active form. But I have a star here on this pathway because there's an enzyme in particular

that I think is worth knowing about. It's called HMG-CoA reductase, which is abbreviated as HMG-CR. It converts HMG-C-A into mevalonic acid, and it is the target to all of the statin drugs. So all of our statin drugs that they push out like candy, target this specific enzyme to inhibit cholesterol synthesis.

Before we talk about the statins in a moment, I just want to say that within the tissues and organs of the body, the liver and the small intestine by far produce the most cholesterol. However, all cells that contain a nucleus do have the ability to turn on cholesterol synthesis if needed. And a few of the other brains that are, not brains. A few of the other tissues that are very, very active cholesterol producers

outside of the liver and small intestine are the brain, adrenal glands, and the gonads, so like the ovaries and the testes. And that should be no surprise in terms of the adrenals and gonads because we need to make cortisol and the corticosteroid hormones in the adrenals, and we need to make the testosterone, the estrogens, the progesterones in the gonads. and so cholesterol again serves as the precursor to all of these molecules in the brain. It's a whole story as well, but we're going to talk about cholesterol in the moment, actually.

So let me circle back to the statins and then I'll get back to the brain. So it turns out, if we look at all of the different statins, there's like probably eight commonly prescribed ones. And we rank them by lipid solubility. So which ones are the most soluble in fat? It goes something like this. Symbastatin, lovastatin, atorvastatin, and all the way down the list, and then the most hydrophilic,

or the least lipid soluble, is resuvastatin. And then, if we look at the statins, and we rank them by the intensity of the side effects experienced by patients consuming them, we see that the lists mirror each other. So the ones that are the highest risk of side effects are simvastin, lovastin, and atorvastin, and the most well-tolerated of the statins is resuvastatin.

This is not a coincidence. So, it turns out one of the major side effects experienced by people on statins is muscle pain and weakness, as well as cognitive decline. Now, as it relates to cognition, it turns out that the more lipid soluble a molecule is, the more readily it can pass through the blood-brain barrier. So it makes perfect sense that our more lipid soluble statins would have an increased access to the brain because they're more readily able to cross through that protective barrier called the blood brain barrier versus our more hydrophilic, water-loving, water-soluble statin like resuvic statin,

is not able to cross that threshold. Therefore, it's not going to cause that cognitive impairment that we so commonly see with the lipid soluble statins. Having said that, they're all poison. They all increase risk of developing insulin resistance. And in patients that already have insulin resistance, statins makes it worse. And so this is just absolute like, you know, it's preposterous when you think about it because we're going to myopically focus on LDL cholesterol, which we're going to talk about what that is in the minute. Without understanding why it could be elevated to begin with, but also not even acknowledging that the benchmark for healthy cholesterol levels has been changed to suit the pharmaceutical

manufacturers. So the old benchmark for total cholesterol was 200, and for LDL cholesterol was around 100. And as the statin drugs rolled out, that bar keeps getting pushed down. and so it's essentially a way to help get more people on the drug essentially because if you push the bar low enough, then everybody can become a patient because everybody's quote-unquote elevated. Meanwhile, it's literally just the benchmark that's been changing. Having said that, though, in insulin resistance and severe metabolic dysfunction, LDL cholesterol can go up, but it's a canary in the coal mine.

It's not something that needs to be drugged down. It's a sign of deeper issues at play, in particular as it relates to the function of the liver, which again, we talked about as this major metabolic hub. So the liver is also the most important organ as it relates to cholesterol packaging and making cholesterol available to the body at large. And so if the liver's metabolism becomes dysregulated

and its ability to sense its environment becomes impaired, now it can't properly understand when it needs to turn off. cholesterol synthesis or not push out more cholesterol into LDL particles, etc. So the notion that cholesterol is causal and having high cholesterol within a moderate range is causal and pathology is not really supported and actually we'd see in people over 65 years old having elevated cholesterol levels, quote unquote, over 150 milligrams per decilator, but even up to 200, is actually protective against all-cause mortality.

and that if you go lower than that, you actually have an increased risk of dying from all causes. And so the whole argument kind of falls apart pretty rapidly when you actually look at the data. Having said that, there is something called ph familial hypercholestrolemia, which is when cholesterol levels can reach up to like 600 milligrams per deciliter. So we're talking like, you know, 3 to 4x, the normal range for cholesterol. This is actually, you know, we have a lot of data showing that ph. correlated with having a heart attack at a young age, essentially, in cardiovascular disease. And this is actually largely because of the role that cholesterol is playing, most likely,

at least in the way that I conceptualize it, because cholesterol helps to add rigidity to cell membranes. It helps to create the actual structure of the membranes. So there's a bunch of cholesterol rafts that float within the cell membranes, and it helps to maintain the structural integrity of cells throughout the body. but if there's too much cholesterol being dumped off and too much cholesterol in membranes, it makes it too rigid. And so I could see that, you know, having many, many downstream effects with regards to how transporters are working in the membrane, how different substrates are being taken up,

how metabolites are being exchanged between cells, etc. So not discounting the fact that familial hypercholestrallyemia is definitely a problem, and there's very clear clinical data to show that, you know, these, individuals would likely benefit from cholesterol lowering medications, whether that's a statin or not. It's kind of another question, though. Obviously, there's lots of other drugs as well. The fibrates, the PCS-K-9 inhibitors, the bile acid sequestrants. There's a lot of different ways that you can kind of get cholesterol out of the body if you got too much. But for the vast majority of individuals, this conversation is like completely moot because most people are within a normal range.

if we were to actually look at what a genuinely normal range is. Okay, so let me move to the next slide. I want to talk about lipoproteins now. Y'all will be familiar with these as well from any sort of blood tests you may have gotten in the past. So our lipoproteins look something like this. They are composed of this, this phospholipid outer layer.

So you can see here we have our phypolypore. phospholipids, they're forming the outside of the lipoprotein. Inside the lipoprotein, we have a combination of triglycerides and cholesterol ester. Chlestrel ester is basically just a storage form of cholesterol. And now on the outside of the lipoprotein, we have cholesterol. We have, of course, our phospholipids. And then lastly, we have our apoproteins. So an apoprotein is a protein identifier for, or a given lipoprotein. What do I mean by that? Depending on what lipoprotein you're looking at,

it's gonna have a different apoprotein that is like a barcode for which kind of lipoprotein we're actually looking at. What are some examples? So we talked about chylomicrons, right? Chylomicrons being the vesicles that are shipping dietary fat that's coming in through the digestive tract into the lymphatic system

and ultimately exchanging with the bloodstream. and that fat is again being carried to the tissues, to the adipose tissue cells for storage, et cetera. So chylomicrons, their structural proteins, so these apo proteins are inherent, meaning that they're required for the lipoprotein to form. The structural apo protein for chylomicrons is called APOB48. It's called APOB48 because it contains an APO, it's an APOB protein, but it has 48% of the molecular weight of ApoB100. So that'll make sense in a moment, but anyways,

the chylomicron is the biggest, as you can see over here as well. It's a huge particle. It's got a lot of triglycerides or triaclycerols. That means the same thing. It's got some cholesterol. It's made with these phospholipids around the perimeter, and we have our apoproteins embedded within that membrane as well. So that's the chylomicrons.

The next step down is VLDL. So VLDL particles are made in the liver. How do we know? Well, it turns out because the structural protein for VLDL particles is APOB. ApoB is the one that you'll maybe have on a lab test and that Peter Othia never shuts the fuck up about. Pardon my French. Its official name is APOB 100 because this is kind of the reference protein.

So whereas APOB 100 has its full structure, the APOB 48 in kilomicrons is 48% of the molecular weight. So it's about half as big as the APOB version that is on VLDL, IDL, and LDL particles. This is also useful, I would say, because when you're, let's say, taking somebody's blood, you can look for these APO proteins as a way to indirectly determine the concentration of the lipoproteins in their blood. So whenever you're quantifying APOB-48 in the bloodstream, each molecule of APOB-48 is going to be one chylomicron, right?

Because each chylomicron has one molecule of APOB-48 present. In contrast, and also, wait, before I move on, APOB-48 is only made by enterocytes within the small intestine. So whenever you see APOB-48, you know that particle came from the small intestine, and that it's a chylomicron. In contrast, only the liver makes APOB 100. So whenever we are quantifying APOB particles, as you might in a lab test, the number of APOB molecules that you quantify in the lab

is telling you the total number of VLDL plus IDL plus LDL in the bloodstream. And if that person is significantly fasted for at least eight hours, the vast majority of those particles should be LDL, with a small fraction being IDL as well. So the VLDL stands for very low density lipoproteins. The IDL is intermediate density lipoproteins, and LDL is low density lipoproteins.

VLDL are kind of a remnant of repackaged chylomicrons, I guess you could say. So you can see, oh, they didn't show it there, but the VLDL it basically has an intermediate amount of fat and cholesterol in it. It's still, it's smaller than kind of microns for sure, but it's bigger than our LDL molecules. And the longer fast that you are, the more these VLDL go down. And so the assumption is when you get an APOB panel done at like LabCore or whatever, that you're primarily measuring LDL when you're doing that. and by the way, you might be wondering what some of these other shapes are. So there are other apoproteins that can be slapped onto a lipoprotein.

I know these names can get a little bit confusing. The lipoprotein is the entire structure. The apoprotein is like a little tag that's added on to the lipoprotein to provide information about its identity. And these apo proteins have different functions as well. So, for example, in the chylomicron, you might have APOE. you might have APOA1, you might have APO C2. All of these APO proteins can be present on the chylomicron.

Versus on the VLDL, we have some APOE and APOC2 in addition to APOB 100. On the IDL, we have some APOE and APOB 100. And by the way, if you're thinking APOE sounds familiar, you may be thinking about this whole area of research about like early onset dementia and APOE4 alleles. And this is all related, exactly. This is all related. And maybe at some point, we will double-click on what the functions of these different

apoproteins are, because maybe it'll make more sense. Essentially, it boils down to fat transport in the brain. So individuals with APOE4 compared to E2 or E3, they have different flux through the fat shuttling and transport mechanisms in the brain, which may be related to things like, I don't know, the glimphatic system or cell membrane dynamics, things like this. Why is it considered inflammation marker LP L.P. L.P. L.P. L.A.A. is not indicated here. So this is APOA1. A1. APOA1 and APOA in general, big capital A, yeah, is a completely different protein from LPLA.

So LP little A is actually the result of a genetic mutation. So the vast majority of the population don't have meaningful levels of apolitelae. But some individuals with the mutation can basically overproduce this apolitel A or perhaps there are certain signals from the environment that are turning up its production. I don't know if it's been studied very much. but the apolitelae is more so associated with vascular inflammation and atherosclerosis, so like hardening of the arteries. So for whatever reason, it just seems to be pathogenic in some way.

I'm not an expert on that one at all, but most people don't have meaningful levels, the people that do. Typically, if you live in accordance to all the things that we generally talk about, that can come back into a more normal range. I think this is more so an issue for modern humans that are losing the ability to have their environments help co-regulate their biology. We're kind of isolating ourselves,

and now each tissue is kind of left to its own devices to try to figure out what's going on, especially as it relates to timing. There's actually a reel that I really want to make soon about if you have grandfather clocks, in one room and they're all hanging on the same wall and you have a really big one and then you have like a few small ones. If you set the big grandfather clock and get it going, get that pendulum swinging, all of the little clocks entrain to the big clock if you give it like a day. And the same thing

with our bodies too as it relates to like the master clock in our brains, the SCN, relative to all the peripheral clocks and all the other cells of the body, that timing signal is absolutely critical to entrain and synchronize activities, including metabolic activities, gene expression regulation, et cetera. And when we miss that timing signal, it's like each tissue has to figure it out itself, and it becomes much more vulnerable as a result of that. So, yeah, I mean, I would say,

even if somebody does have, like, the elevated LP little A, you know, their doctor may put them on one drug or another. Typically, I think it's a satin, and there may be something else. LP little A specific at this point. I haven't looked into it in a while. But, you know, there's never recommendations about all of like the common science foundations that we know and love. And that's like ideally the place to start whenever anything is going wrong is to really dial in those basics to the endth degree.

And to kind of simplify our lives. Like if we're taking a bunch of supplements or we're, you know, doing a bunch of different kind of things. I think it just really helps to make our lives super simple when things start going wrong or we're experiencing some issues, et cetera, and just really bring it back to the bare bones fundamentals and typically things kind of take care of themselves. Or at least you get some level of clarity around what might be going on. Circadian timing, yes. Yes, yes, yes. The way we're living our lives on the day to day makes the biggest difference in our health because it's what's routinized. It's what we're engaging. It's the stimuli in the environment that we're engaging with the most. So those are the things.

things we need to pay the biggest attention to or the things that are going to be exposures, like the vast majority of our days, because if those environments aren't good, then it's just going to be wearing and tearing on us instead of building us up over time. Okay. And then finally here, I want to mention HDL particles. Of course, these are the quote unquote good cholesterol, it's typically called. HDL molecules can have a variety of different APO proteins. The ones indicated here are APOE, APOA1, and typo c2. HDL particles are largely phospholipids. So if we compare the composition here, kilomicrons are about 98% triglyceride, LDL particles are about 60% cholesterol, 15% triglyceride,

and 25% phospholipid. And HDL molecules or particles are about 10% triglyceride, 30% cholesterol, and 60% phospholipid. And canonically, the HDL particles are seen, as retrograde cholesterol delivery. So whereas typically, canonically, LDL particles are seen as taking cholesterol from the liver and dropping it off elsewhere, the HDL particles are seen as taking cholesterol from the peripheral tissues and bringing it back. And having said that, though, I will say that I feel like our understanding and conceptualization of lipid metabolism, as it really is.

to cholesterol management and cholesterol storage, etc., is like very overly simplified and rudimentary. I think there's way more going on than we know. But just so that y'all are familiar with the general idea of lipoproteins and why these show up on labs and what you're actually looking at when you see these molecules and their functions. So we'll see how, you know, their potential functions

kind of expand over time, but to be determined. All right, let's talk a little bit about fat storage. So we talked about how when you're eating, that fat's getting, you know, put into chylomicrons, then shuttle into the lymphatic system and then throughout the body. So what happens when we are in this fed state as it relates to fat? So we're in the fed state. That means insulin is being produced, assuming it's a mixed meal. So we have insulin binding to the insulin receptor in our.

white adipose cells, so our fat tissue. When insulin binds, it stimulates the inhibition of lipolysis. So lipolysis is the pathway that breaks down triglycerides, into glycerol, and free fatty acids. Insulin is saying, hey, we have nutrition, we have energy coming in. That means, you know, you can shut off your lipolysis. We're going to store that for later. Instead, we want to make new fat. And so insulin while inhibiting lipolisus can go ahead and activate de novo lipogenesis, which is the formation of new triglycerides within the fat cell. And so the fat cell can expand to accommodate those new triglycerides. There's definitely like an endocrine aspect of fat tissue as well.

So this graphic notes that the white adipose tissue creates and releases adipocines or dipocytes. the adipokines are kind of these endocrine factors that can go into the blood and signal to other tissues about what's going on in the fat, which is interesting. And like a lot of these tissues have their own cytokines. Like myokines are factors produced in the muscle that can send signals to the brain, to the fat tissue, to the liver, about what's going on in the muscle, for example. simultaneously when insulin binds the insulin receptor in the liver cells, we are again increasing glycogen synthesis, we are inhibiting the breakdown of glycogen, and we are inhibiting gluconeogenesis as well. And so the production of glucose in the liver gets shut off when insulin binds, and the synthesis of our stored sugar in the liver will go up, which is just simply in

response to that signal of energy and carbohydrate abundance that is insulin. Okay. In contrast, if we're talking about fat mobilization in a fasted or low-carb availability state, we can talk more about glucagon. So glucagon being that on the teeter-totter opposite to insulin. So glucagon binds to its receptor. It stimulates the signal transduction pathway that we talked about before, so protein kinase A, PCA.

And there's this whole cascade that basically leads to the activation of hormone-sensitive lipase, which then stimulates the breakdown of triglycerides into our free fatty acids and glycerol backbone. The free fatty acids and the glycerol can then leave that fat cell and go into the bloodstream. The fatty acids can be transported on albumin once again. and then we have specific fatty acid transporters that are available on cells like muscle, etc. That are there as doorways for those fats to enter.

And once those fats enter the new cell to be burned, they can undergo beta oxidation and ultimately support ATP production. So what is beta oxidation look like? Here's our fatty acid oxidation pathway. This is happening within the mitochondria. So fatty acids are entering, let's say it's our muscle cell, for example, and we're, we have these fatty acids, they're entering into the mitochondria. Well, actually before that, they're entering into the cell.

And they first need to be activated into this fatty acyl-CoA molecule that can then combine with carnitine to form this activated form of fat, which can then pass through this. outer membrane and get into this intermembrane space. So that's the acyl carnitine here. Once we have the acal carnitine, then we're passing into the mitochondrial matrix through that inter mitochondrial membrane. So the acyl carnitine can then be converted by this enzyme CPT to carnitine pometoyal transferase 2 into a fatty acyl co-A and then that free carnitine gets released. So the carnitine is actually serving as the shuttle here. Without this carnitine molecule, and maybe you've seen that supplement L. Carnitine in the store, maybe you've taken it before. You can get it,

obviously, from eating meat. But the reason that carnitine supports fat burning, like it's often marketed, is because it serves as the shuttle for the fat molecule to ultimately get into the mitochondria. without this carnitine group being added onto that fat chain, those fat carbons would never be able to reach into the inner matrix and actually undergo beta oxidation. So the carnitine gets released and recycled back to the cytosol after the molecule reaches into the matrix. And then this fatty acylcoa undergoes multiple steps of kind of activation and conversion

in order to release two carbons a two-carbon group from the backbone. So if you start with palmitate, which is a 16 carbon fat, by the end of this one round of beta oxidation, you would then have 14 carbons, and you're releasing a two-carbon group in the form of acetyl co-A. So this part of the pathway is what we would call as beta oxidation. And that's because you're literally oxidizing the fat at the beta carbon. So the alpha carbon would be the last carbon in the change. the beta carbon would be the second carbon. So you're lobbing off the last two carbons of the fat.

That's now acetylCoA, which is then able to directly enter in to the carbonylaclylic acid cycle, the TCA cycle, which again, acetylacetciccid to form citrate in that first step of the TCA cycle. And then this can just keep repeating until the fat gets to a short enough length, essentially, or until the cell doesn't need any more of these two carbon units in the form of acety acety co-a. And so these fatty acyl-Coase, we're starting with one, we're ending with one that's just less two carbons, can also enter into ketogenesis as well, depending on how rapid beta oxidation is happening. So on that note, let me go over that with y'all. So ketone body synthesis and oxidation.

These are our ketones. Beta hydroxybutyrate or three hydroxybutyrate is the primary circulating ketone body. Acetoacetate is also a circulating ketone body, but it's at a much lower level than beta hydroxybutyrate. And acetone is the spontaneous breakdown product of acetoacetate in the blood. So essentially just based on like temperature and entropy, this acetone group can break off of acetoacetate and this gets breathed out via the lungs because it's a very volatile molecule acetone. And this is why people who are in deep ketosis, they have that certain smell to their breath. And even when I'm personally in ketosis, I can feel like the volatile, like there's something volatile in my breath when I breathe out. I can feel it.

And it's very similar to, like, if you have a bottle of nail polish remover, which is what acetone is, and you smell it. It has, like, this very warm, volatile sensation in your nose. That's kind of what it feels like, but to a much lesser extent, when you're in, like, deep ketosis and you're breathing out, you can kind of feel this solvent-like behavior and this very warming, volatile sensation in your airway. So that's acetone. And now let's talk about how we're making these. ketones. So in the liver, which is where ketones are primarily produced a little bit in the

kidney, but by and large, the liver is the primary producer, again, as our hub of metabolism. We have acetylcoa that we're making largely from fatty acid oxidation because ketones really aren't going to be able to be made from any other substrate because no other substrate will be as plentiful and can produce as much acetyl co-a as fat oxidation because, you know, a single molecule of palmitate, C-16, has eight two carbon units in it, right? So you're able to make way more acetyl-CoA from fat compared to breaking down amino acids or glucose. And so as this acetyl-CoA begins accumulating during rapid fat oxidation, which is what's happening when your carbohydrate restricted or you're fasted for 24, 48 hours or so. This acetyl-CoA starts

building up fast enough to be able to push it through this pathway of ketone synthesis. So first it goes through thylase to make acetoacetyl-CoA. Then it goes through HMG-CoA synthase to make HMG-G-CoA. Then it goes through HMG-G-CoAeys to make acetoacetate. Acetoacet can be directly put into the bloodstream at a certain rate, but a large fraction of it will be converted into three hydroxybutyrate or beta hydroxybutyrate, and that can also be put it into the bloodstream. And this is also why I told y'all that one readout for liver redox status is the ratio in the blood of acetoacetate to three hydroxybutyrate.

That's because this last step here involves the conversion of NADH to NAD plus. So if we look at the ratio of acetoacetate to three hydroxybutyrate, it's a proxy for the ratio of NADH to NAD plus in the mitochondria of the liver cells. So more interesting on a research basis, I would say, but it's just kind of a fun fact there. So again, this 3HB and acetoacetate can go into the bloodstream. Some of that acetoacetate will be lost to acetone. But then they can both be taken up by peripheral tissues, including the muscle, the brain, the pancreas, the spleen, the heart. most of the tissues will use and take up ketones.

And once they get into the tissues, now the process is undone in actually a couple shorter steps. So when three hydroxybutyrate enters a tissue, it gets converted back into acetoacetate, making NADH in the process. Then acetoacetate can be converted into acetoacetal-CoA, which is then directly converted into two molecules of acetylCoA, which can then both enter into the TCA. cycle. So this is how the ketone bodies are metabolized. This side is how they're made. This side is how they're metabolized. This is just a broad overview of what I just described. Kind of what the substrate is,

the steps, how it's transported. This is saying heart, but you could say any number of tissues there. You could say brain. You could say pancreas. You could say spleen. You could say muscle. All of them are using ketones to a certain extent, depending on their, you know, the time of day, their activity levels, the health status of the organism. So in heart failure, ketone body oxidation in the heart actually increases. And I think that that's likely an adaptive mechanism to help the heart survive a bit longer because, again, it's serving as an important fuel substrate. And it's a very efficient one as well.

So these are the ketone bodies. This is how they're used. I guess one thing I'll mention really briefly is diabetic ketoacidosis. So the reason that that happens is because, again, the livers are hub, right? So the liver is dictating how much glucose is being made, how many ketones are being made. And so if the liver becomes death to insulin, so the liver can no longer properly sense insulin, it's going to be pumping out blood sugar, but it's also going to start pumping out ketones as well

because insulin is the factor that shuts off ketone production in the liver. Because it's saying, hey, carbs are coming in, energy's coming in. That means we don't need to make as many ketones, right? So not only does becoming deaf to insulin make the liver make too much glucose, but also ketones as well. And interestingly enough, actually, insulin is the major regulator of ketone levels, even in a healthy normal person who's fasting, for example.

So when ketone levels reach a certain threshold amount, maybe it's like two, no, not two. It's probably like three or four millimolar. When it reaches that certain threshold amount, it actually stimulates the pancreatic beta cells to make a little bit of insulin to help tamp down the levels so they don't get too high. Because if they go too high,

these ketones are carboxylic acids, which means they're acidifying the bloodstream, which means that that has, you know, implications with regards to how a lot of things are working because that blood needs to stay within that 7.35 to 7.45 range. And when it leaves that range, whether it's too low or too high, it begins to wreak havoc on oxygen transport and nutrient metabolism, et cetera. So in diabetic ketoacidosis, that's happening because it's like a runaway freight train of ketone production and glucose production at the same time by the liver who is now deaf to insulin.

And so I just wanted to mention that to y'all because it's, I think, relevant to, or and also maybe interesting, physiologically speaking. Yes. Okay. Let me see. So I wanted to show you all my paper, but I feel like, give me one second here. I feel like it's getting super late. So I might have to put it off once again. Let me just see one thing really quick. I wanted to add a question to your...

Test your synthesis. Where is it? Oh, here it is. Just give me one second. Okay. Okay, okay. Where are you? All right.

This is my paper. We're going to go through it. Maybe we'll go through it at the beginning next week, just so we make sure we have time, because I think y'all will really be able to appreciate. exactly what we did and understand the methods as well. So I'll show you all that next week. Unless you want to get a teaser, feel free to look at it at any time.

The link is here. But for now, the tester synthesis questions for next week, number one, name three different types of lipids and their functions. Number two, what is the function of bile as it relates to digestion? Number three, name three different lipoproteins. What distinguishes them from one another? Number four, what enzyme in cholesterol synthesis do statins, hit. Number five, what molecule is required to shuttle fat into the mitochondria to undergo beta oxidation.

Number six, what does insulin do to lipolisus and adipose tissue? What does glucagon do? Number seven, what organ synthesizes the vast majority of ketone bodies? And number eight, what is the substrate for ketone body synthesis? So those are your questions for next week. I hope you all loved today's lecture. I feel like it was a very very very. at least to me, I love nerding out in this stuff. I feel like it's super applicable and just, like, highly relevant to life and health and also just very intellectually stimulating and scientifically interesting. So I'm really glad you all could come and, yeah, hopefully you'll learn some things and enjoyed it.

And we'll continue the fun next week. I have to go back to my lesson plan to figure out what we're going to be talking about. But we're definitely going to open up with my paper. So you can look forward to that. And then we'll continue with our bio cam. I'm hoping to wrap up by the end of the month. And then take like two to three weeks off before we begin again in semester two with our anatomy and physiology lectures, which Roa is going to come give a guest lecture. So I'm really, really excited.

And cannot wait to do that. So for now, that's all I have for y'all. And I look forward to seeing you next week. Thank you. Bye