How does that hamburger become a cholesterol issue? Let’s begin by finding out how the “cholesterol” is transported into the body, and what role HDL plays.
It all starts with chylomicrons—in general, chylomicrons carry exogenous (that hamburger) lipids (fats) from the intestine to the rest of the body. The remaining lipoproteins are involved in transporting endogenous lipids (fats the liver makes) to different organs.
Triacylglycerols (TAGs) are made up of a variety of fats such as saturated, monounsaturated, trans, and omegas fats, to name a few. TAGs dominate chylomicrons and VLDL, whereas cholesterol dominates LDL and HDL. And because cholesterol dominates LDLs, this is part of the reason why LDL is wrongly named LDL-cholesterol. Not to put too fine a point on it, LDLs predominantly contain esterified cholesterol (E-Col).
Point of interest: The difference between free and esterified cholesterol; free cholesterol is biologically active and has cytotoxic effects, whereas esterified cholesterol (E-Col) the majority of cholesterol LDLs contain, are a protective form for storage in the cells and transporting in plasma .
Endogenous fat transport system overview (Making the Chylomicrons, i.e., Fat Transporters):
1) Cells called the endoplasmic reticulum (ER) of the intestinal mucosa pack together TAGs, a small amount of cholesterol, and phospholipids into chylomicrons in an organised arrangement that also includes fat-soluble vitamins into a protein transporter called apo B-48. The apo B-48 is important because it forms the structure and stabilises the chylomicrons. The apo B-48 is similar to a ship’s cargo container, and it carries the lipids into the blood. In the B-48 container are the lipids: TAGs (fatty acids and essential fatty acids) represent 88%, phospholipids 8%, cholesteryl esters 3%, and free cholesterol 1%. Fat-soluble vitamins absorbed in the intestinal lumen are also incorporated in the chylomicron core.
TAGs inside the chylomicrons are of great importance to us because they become the building materials and signalling metabolites that we need in the correct ratios. These TAG’s contain saturated, mono, and the omega fats, we need to get this right. The great news is this, the omegas are required in extremely small quantities, so it’s not difficult to put this together. I’ll bring this together with the framework later, so forget the specifics, again, it’s simple.
After the container is loaded, its status is set to nascent (immature); they’re not yet ready to unload their cargo just yet as it requires two more apo protein, apoE, and apoC-II. Chylomicrons having a diameter of 100–500 nm, appear in blood around one hour after we eat by passing through the lymphatic system. They’re carried to capillaries that lead them to the thoracic duct and the subclavian vein to reach our blood supply; this is epigenetics in action. When the chylomicrons meet up with HDL particles in blood circulation, the HDL’s supply two critical cofactors, apoE and apoC-II, and then they become mature and functional. Well, that is if they’re not oxidised by destructive metabolites such as AGE’s, ALE, and aldehydes, then they’re kind of useless, and this becomes a big P2 problem.
Chylomicrons hang around in circulation for more than eight hours after fasting depending on cargo status, endothelial status, endoplasmic reticulum status, insulin status, thyroid status, nutrient partitioning capabilities, and whether or not the delicate apo’s are taken out by free radicles. Their main role before reaching the liver is to drop off TAGs. In circulation, chylomicrons are processed in the blood vessel endothelium, where they interact with lipoprotein lipase (LpL), an enzyme that is activated by apo C-II supplied by HDL and transforms the TAGs to free fatty acids (FAs). Then the FAs are taken up by sites that have LpL enzymes such as adipose tissue (fat cells, storage), myocardium (heart cells, energy), the skeletal muscle (energy), which is the biggest glucose disposal system in the body and lactating mammary glands.
In adipose tissue, FAs are esterified back to TAGs for storage and later use, for winter, right. In skeletal and cardiac muscles, FAs are oxidised for energy production. Lastly, in mammary glands, they are used to synthesise TAGs for the baby. Glycerol makes its way back to the liver and can be converted into glucose, glycogen, and used for energy.
Once mature chylomicrons have dropped off the majority of their cargo, they give the apoCII back to the HDL particle, and the chylomicrons then become remnants and bind to a receptor of the liver for recycling. Pretty efficient.
The diagram below is an overview of how the food we eat form chylomicrons (lipid transporters) depicted in blue.
(1) The hamburger is broken down into fats, carbon, electrons, vitamins, and so on.
(2) All the fat-soluble components are packaged up in chylomicrons and enter the lymphatic system.
(3) HDL acting as a cofactor supplies the nascent (immature) chylomicron two critical Apos (APO-CII — APO-E) and then, and only then do the chylomicron become fully mature and drop off their cargo. This is one reason why HDL is super important. Without HDL acting as a cofactor, you cannot drop off the vitamins to your organs and tissues. You cannot drop off fats to muscles and heart for energy. The heart prefers fat as an energy source. Instead, the chylomicron drops off all its cargo at the liver, and it becomes a messy process that ADDS fuel to the fire – Inflammation.
(4) Once mature, the chylomicrons drop off free fatty acids to the heart, working muscles and adipose tissue, they return the Apo-C-II to HDL.
(5) Finally, the chylomicron becomes a remnant particle and is recycled by the liver.
Interestingly, the chylomicron is a cell too, and its first line of protection is yep, you guessed it—the bilayer. It also needs an omega-6-3 ratio of 1/1 to have superior protection. More on how to achieve this soon, and it’s not difficult.
What is the bilayer? And why is the omega-6-3 ratio important? The Winter Diet is why.
It’s time to explore and see what happens to an oversupply of food.
A quick pass at the biochemistry to shine the torch on the mitochondria and look at its TCA cycle energy sensor, isocitrate dehydrogenase to explore how it indirectly helps create the next important protein transporter, VLDL when they’re an oversupply of food in circulation.
When we have an abundance of energy being processed in the mitochondria, an enzyme called isocitrate dehydrogenase signals energy to exit the mitochondria and synthesize fat to be stored away in the adipocytes, and other lipids to be created such as cholesterol.
The below image is a simplistic look into the endogenous lipid transport system, or when the liver turns food into fat. Again, chylomicrons follow the same life-cycle and are being used as a proxy here.
Point of interest: It’s normal to make fat consuming most meals, if you want to lose body fat with ease, I provide the steps to optimise our four main hormonal systems in the framework section of my book. Grab it on Amazon.
Interestingly, liver receptors that bind to LDL for recycling change dynamically based on thyroid health. If our thyroid function is low, gene expression lowers the number of liver receptors, thus your ability to clear LDL’s from blood circulation. So a person with poor thyroid function will have a problem, and this can contribute to high LDL. [R]
One: Once the cell has detected a surplus of energy, and lipids are packaged up in a VLDL protein transporter the same way chylomicrons are. However, the liver uses another apoprotein called apo B-100, which forms the structure and stabilises the VLDL.
Two: After that, the VLDL is sent out into circulation, and like the chylomicrons, it needs HDL to supply two critical cofactors, apoE and apoC-II, and then it becomes mature and functional.
Three: The VLDL is now able to drop off the triacylglycerols (TAG) to extrahepatic cells such as adipose tissue (fat cells) and myocytes (muscle cells), both heart and skeletal muscles. In the capillaries of these tissues, LpL releases the TAG’s, and they’re transformed into free fatty acids and glycerol. Besides the metabolism of TAG by LpL acting on apoC-II, VLDL exchanges TAGs for cholesterol esters from HDLs. The FAs are sent to myocytes for energy or adipose for storage. Glycerol is transported back to the liver to make lipids, energy, more glucose, or glycogen for safe storage.
At this stage, VLDL particles have dropped off much of their TAG, and the bulk of their load is now cholesterol, and VLDL becomes smaller, and as it becomes smaller, its surface phospholipids are transferred to HDL. After these changes in size take place, apo C-II returns to HDL, and the action of LpL is interrupted. The half-life of VLDL is of approximately four hours during this process and becomes IDL.
Four: IDLs are packed in cholesterol, mostly esterified, and with small amounts of TAG. Their apoproteins are B-100, and E. Receptors in the liver bind apo E and metabolise over half of the IDL particles from the blood. Because IDLs lack apo C-II, LpL cannot extract the TAG present in IDL blood circulation. However, the liver can extract TAGs by a process called liver lipase, and it takes up the FAs. From there, the apo E is returned to HDL, and all these changes transform IDL into LDL. IDL can remain in the blood for around two to five hours.
Five: LDLs predominately contain esterified cholesterol and a single apoprotein, the apo B-100 on its bilayer, so it’s extremely vulnerable in a high omega-6-3 system with lots of nasty P2s.
What do the remaining LDLs do? Well, the LDLs bind to receptors that have an apo B-100 LDL receptor on the surface of all cells. In these cells, LDLs are broken down into the following products, including amino acids, cholesterol, and FAs. In some cells, cholesterol is added to the cell membranes, while, in others (such as the adrenal cortex, ovaries, or testes), it’s used to make glucocorticoids and sex hormones. The excess is esterified and stored in the cell. So, the LDL is the final product of VLDL and has a lifespan of around 2.5 days.
Fats are complex and not equal; each fat has a specific and often multifaceted role. As complex as those five points above are, we can BYPASS that whole LDL conundrum and use therapeutic fats such as medium-chain triglycerides (MCTs) to kickstart fast fat loss. The problem with fats having a carbon length greater than 12 (long-chain) is a royal pain in the arse for the body to use.
And these LDL particles and cause a lot of trouble along the way as you’ll soon learn when we explore the next section, the lipid system goes rogue.
The MCT advantage. MCTs, mimic glucose by providing instant energy. MTCs have further advantages, such as a calming effect. Decanoic acid, a component of medium-chain triglycerides, helps to calm the brain by binding to and inhibiting glutamate neurotransmitters 1.
MTCs also has fewer calories than long-chain fats. For example, one mol of the MCT caprylic acid (8 carbons) yields 61 moles of ATP, whereas one mol of palmitic acid (16 carbons) yields 129 moles of ATP. What that means is, caprylic acid has similar calories to glucose and half that of their long-chain cousin.
A point for nursing Mums, the main FA used in breastfeeding is decanoic, or capric acid. Fatty acids in breastmilk have a chain length of 6 to 10 carbons, which gives them the advantage of easier absorption. Scientists in the field say it’s important for infants and young children because these FAs bypass the lipid transport system, and directly transferred to the bloodstream without having to pack them into long and complex chylomicrons system.
Caveat: However, don’t go too hard with them MTCs because they can cause problems with some unpleasant gut irritations, and long-chain fats have many health benefits. Please get advice because not one size fits all.
Six: The lipid system goes rogue.
Within a rogue lipid system, we have the below issues to circumvent.
- An omega-6-3 ratio that promotes inflammation and insignificant production of resolvins, protectins, or masiens to resolve inflammation and trigger powerful endogenous defense systems.
- The P2 burden, light.
- The P2 burden, heavy.
- Thyroid health expressing fewer LDL receptors for LDL recycling on the livers surface
- Oxidative stress.
- Enzyme dysfunction, such as the enzyme LCAT for HDL, which we’ll explore later.
- Finally, as we progress through the tail-end of this section, LDL particle size and count play a critical role, and current lipid panels do not screen for which is a huge problem. For example, someone with a 100 cholesterol may have 300 LDL particles, but more predictive is, another person could have 100 cholesterol with 1000 particles, which is a bigger predictor of CVD. The latter has P2s wreaking havoc.
Let’s begin at the bilayer, where the majority of those problems arise.
VLDLs, LDLs, and chylomicrons have a layer of protection, which I have been slowly revealing. As we know, the ratio of omega-6-3 is important, and the researchers have shown us that ideally, the ratio should be 1/1 or 2/1. What’s fascinating to me is that when the gut makes chylomicrons, it incorporates omegas into the bilayer, and so does the liver, from VLDL to LDL.
Knowing that we can now appreciate that in multiple situations, LDLs are proatherogenic, meaning causing cardiovascular disease (CVD).
Recall earlier that the phospholipid bilayer has a few main players: Cholesterol, phospholipids, saturated, unsaturated fats (omegas), and sphingolipids.
Because the line of defense is primarily driven by eicosanoids such as AA and EPA, and because the role of resolvins, protectins, or masiens are driven solely by DHA and EPA, the focus will be on the omegas; they are the superstars in defense.
The bilayer is the first line of defense, and our cells need protection from the following: AGE’s, ALE’s, aldehydes, reactive oxygen species (ROS) and reactive nitrogen species (RNS).
Point of interest: Aldehydes, such as 4-hydroxynonenal, are exponentially more toxic than ANY eicosanoid that our body produces to fight bacterial and viral infections. Stronger than the grenade AA throws around. So, eliminating the majority of these aldehydes then becomes important.
If you’d like more information, it’s all in my book.