The Blood Lipids: Cholesterol and Triglycerides
Figure 1: Steroid Biosynthesis Pathways7
Cholesterol is a wax-like steroid molecule that plays a critical role in metabolism. It is a major component of cellular membranes, where its concentration varies depending on cell type. For example, the lipid portion of the membrane of liver cells consists of about 17% cholesterol, while that of red blood cells consists of about 23%.8
The cholesterol in cell membranes serves two primary functions. First, it modulates the fluidity of membranes, allowing them to maintain their function over a wide range of temperatures. Second, it prevents leakage of ions by acting as a cellular insulator.8 (Ions are molecules used by cells to interact with their environment.) This effect is critical for the proper function of neuronal cells because the cholesterol-rich myelin sheath insulates neurons and allows them to transmit electrical impulses rapidly over long distances.
Cholesterol has other important roles in human metabolism. Cholesterol serves as a precursor to steroid hormones, which include the sex hormones (androgens and estrogens); mineral-corticoids,9 which control the balance of water and mineral excretion in the kidneys; and glucocorticoids, which control protein and carbohydrate metabolism, immune suppression, and inflammatory processes (Figure 1).7 Cholesterol is also the precursor to vitamin D. Finally, cholesterol provides the framework for the synthesis of bile acids, which emulsify dietary fats for absorption.
Triglycerides are storage lipids that have a critical role in metabolism and energy utilization. They are molecular complexes of glycerol (glycerin) and three fatty acids.
While glucose is the preferred energy source for most cells, it is a bulky molecule that contains little energy for the amount of space it occupies. Glucose is primarily stored in the liver and muscles as glycogen. Fatty acids, on the other hand, when packaged as triglycerides, are denser sources of energy than carbohydrates, which make them superior for long-term energy storage (the average human can only store enough glucose in the liver for about 12 to 24 hours worth of energy without food, but can store enough fat to power the body for substantially longer).10
Lipoproteins: Blood Lipid Transporters
Lipids (cholesterol and fatty acids) are unable to move independently through the bloodstream, and so must be transported throughout the body as lipid-protein complexes called lipoproteins. Contained within these lipoproteins are one or more proteins, called apolipoproteins, which act as molecular "signals" to facilitate the movement of lipid-filled lipoproteins throughout the body. Lipoproteins can also carry fat-soluble nutrients, like coenzyme Q10 (CoQ10), vitamin E, and carotenoids, which protect the transported lipids from oxidative damage. Vitamin E and CoQ10 also help prevent the oxidative modification of LDL particles, which in turn protects the blood vessel lining from damage. This will be discussed in greater detail later in this protocol.
There are four main classes of lipoproteins, each with a different, important function11:
- Chylomicrons are produced in the small intestines and deliver energy-rich dietary fats to muscles (for energy) or fat cells (for storage). They also deliver dietary cholesterol from the intestines to the liver.
- Very low-density lipoproteins (VLDLs) take triglycerides, phospholipids, and cholesterol from the liver and transport them to fat cells.
- Low-density lipoproteins (LDLs) carry cholesterol from the liver to cells that require it. In aging people, LDL often transports cholesterol to the linings of their arteries where it may not be needed.
- High-density lipoproteins (HDLs) transport excess cholesterol (from cells, or other lipoproteins like chylomicrons or VLDLs) back to the liver, where it can be re-processed and/or excreted from the body as bile salts. HDL removes excess cholesterol from the arterial wall.
Among its myriad of functions, the liver has a central role in the distribution of cellular fuel throughout the body. Following a meal, and after its own requirements for glucose have been satisfied, the liver converts excess glucose and fatty acids into triglycerides for storage and packages them into VLDL particles for transit to fat cells. VLDLs travel from the liver to fat cells, where they transfer triglycerides/fatty acids to the cell for storage. VLDLs carry between 10% and 15% of the total cholesterol normally found in the blood.12
As VLDLs release their triglycerides to fat cells, their cholesterol content becomes proportionally higher (which also causes the VLDL particle to become smaller and denser). The loss of triglycerides causes the VLDL to transition to an LDL. The LDL particle, which averages about 45% cholesterol, is the primary particle for the transport of cholesterol from the liver to other cells of the body; about 60‒70% of serum cholesterol is carried by LDL.12
During the VLDL to LDL transition, an apolipoprotein buried just below the surface of the VLDL, called ApoB-100, becomes exposed. ApoB-100 identifies the lipoprotein as an LDL particle to other cells. Cells which require cholesterol recognize ApoB-100 and capture the LDL, so the cholesterol it contains can be brought into the cell. Each LDL particle expresses exactly one ApoB-100 molecule, so measurement of Apo-B100 levels serves as a much more accurate indicator of LDL number than LDL cholesterol level.13
LDL particles are brought into cells via LDL receptors, and the more these receptors are active, the more LDL particles are removed from the blood resulting in a lower blood concentration of LDL.14 The enzyme PCSK9 (proprotein convertase subtilisin/kexin type 9) degrades the LDL receptor. PCSK9-inhibitor drugs that are antibodies against this enzyme have been developed, and they markedly lower LDL cholesterol.
Because of the correlation between elevated blood levels of cholesterol carried in LDL and the risk of heart disease, LDL is commonly referred to as the "bad cholesterol." LDL is, however, more than just cholesterol, and its contribution to disease risk involves more than just the cholesterol it carries.
All LDL particles are not created equal. In fact, LDL subfractions are divided into several classes based on size (diameter) and density, and are generally represented from largest to smallest in numerical order beginning with 1. The lower numbered classes are larger and more buoyant (less dense); size gradually decreases and density increases as the numbers progress. Smaller, denser LDLs are significantly more atherogenic for two reasons: they are much more susceptible to oxidation,15-17 and they pass from the bloodstream into the blood vessel wall much more efficiently than large, buoyant LDL particles.18 A more comprehensive lipid test, such as the NMR LipoProfile,6 allows for assessment of the size and density of LDL particles, a feature that increases the prognostic value and sets these advanced tests apart from conventional lipid tests. If an individual is found to have a greater number of small dense LDLs, they are said to express LDL pattern B and are at greater risk for heart disease than an individual with more large buoyant LDL particles, which is referred to as pattern A.
Lipoprotein(a), also called Lp(a), is a subclass of lipoprotein particles composed of LDL-like particles bound to another particle, called apolipoprotein(a). Lp(a) is a known marker of cardiovascular risk; that is, elevated levels correlate with greater risk for cardiovascular disease. Lp(a) levels are mostly determined by genetics (as opposed to diet and lifestyle as with other blood lipid markers). Generally, Lp(a) levels above 50 mg/dL (~125 nmol/L) are considered to indicate high cardiovascular risk, whereas levels below 30 mg/dL (~72 nmol/L) are associated with low risk.19
Lp(a) levels should be interpreted in the context of other cardiovascular and lipid risk markers, and family history of cardiovascular disease is an indication for measurement of Lp(a). As of mid-2019, no reliable data from randomized controlled trials have shown that targeting Lp(a) reduction with medication is an effective risk-reduction strategy. As of this writing, the only intervention available that appears promising for lowering Lp(a) is lipoprotein apheresis.20 Lipoprotein apheresis involves the removal of lipoproteins from the blood via a blood filtration process used only in people with very elevated blood lipids despite maximal lifestyle and drug therapy. Thus, Lp(a) is primarily useful as a marker for identifying people who might benefit from adopting a more intensive overall cardiovascular risk reduction strategy.
Nevertheless, some intriguing interventions that target Lp(a), such as antisense oligonucleotides, are currently under development and may represent a novel intervention if research progresses as hoped, but further studies are needed.5,21-23
HDLs are small, dense lipoprotein particles assembled in the liver. They carry about 20‒30% of total serum cholesterol.12 Cholesterol carried in the HDL particle is called "good cholesterol," in reference to the protective effect HDL particles can have on cardiovascular disease risk. HDL particles can pick up cholesterol from other tissues and transport it back to the liver for re-processing and/or disposal as bile salts. HDL can also transport cholesterol to the testes, ovaries, and adrenals to serve as precursors to steroid hormones. HDLs are identified by their apolipoproteins ApoA-I and ApoA-II, which allow the particles to interact with cell surface receptors and other enzymes.
The movement of cholesterol from tissues to the liver for clearance, mediated by HDLs, is called reverse cholesterol transport. If the reverse cholesterol transport process is not functioning efficiently, lipids can build up in tissues such as the arterial wall. Thus, reverse cholesterol transport is critical for avoiding atherosclerosis.
Testosterone and Reverse Cholesterol Transport
Interestingly, a link has been observed between the male hormone testosterone and reverse cholesterol transport; that is, testosterone enhances reverse cholesterol transport. Though it is known that testosterone decreases levels of HDL, it also improves HDL function. This effect is mediated by a protein in the liver called scavenger receptor B1 that acts to stimulate cholesterol uptake for processing and disposal. Testosterone beneficially increases scavenger receptor B1.24 Testosterone also increases the activity of an enzyme called hepatic lipase, another facilitator of reverse cholesterol transport.25
Aging men experience a decline in testosterone levels, as well as an increase in heart disease risk, suggesting these phenomena may be related. Indeed, studies have shown that men with even slightly lower testosterone levels were over three times as likely to exhibit signs of early coronary artery disease.26 Men interested in learning more about the link between heart disease and declining testosterone levels and ways to boost testosterone naturally should read Life Extension's "Male Hormone Restoration" protocol.