21.1 Introduction to Lipoprotein and Apolipoproteins

Understanding Lipids

Triglycerides are the main dietary source of fat. They are composed of three long fatty acid chains attached to a glycerol backbone, as depicted in Figure 21.2. The major sterol in the body is cholesterol. Cholesterol is important for the structure of cell membranes and for the production of hormones, bile acids, and vitamin D.

Figure 21.2 Triglycerides are composed of a glycerol backbone attached to three fatty acid chains. The fatty acids can be stored and released later for energy. (credit: modification of work from Biology 2e. attribution: Copyright Rice University, OpenStax, under CC BY 4.0 license)

Dyslipidemia is the general term to describe abnormal lipid levels or an imbalance of lipids in the blood. Hyperlipidemia refers to excessive serum levels of lipids. It can be categorized as hypertriglyceridemia (excessive triglycerides in the blood) or hypercholesterolemia (excessive cholesterol in the blood). Hypercholesterolemia is extremely prevalent, affecting 11.5%–38.1% of adults in the United States (Centers for Disease Control and Prevention, 2023b; Tsao et al., 2022). Many individuals with hypercholesterolemia have no symptoms; the diagnosis is made by monitoring their lipid panel. Familial hypercholesterolemia is a genetic disorder that manifests as very high cholesterol levels that can cause early cardiovascular disease. People with familial hypercholesterolemia can have one or two copies of the gene for familial hypercholesterolemia. Clients with one copy of the gene have heterozygous familial hypercholesterolemia, which is a mild form of the disease. Clients with two copies of the gene have homozygous familial hypercholesterolemia. This is a much more severe form of the disease and manifests during childhood. Some of the signs and symptoms of familial hypercholesterolemia are bumps or lumps around the knees, knuckles, or elbows; swollen or painful Achilles tendon; yellowish areas around the eyes; and a whitish-gray color in the shape of a half-moon on the outer edge of the cornea, which are lipid deposits called arcus senilis (Centers for Disease Control and Prevention, 2020).

Lipoproteins

Lipoproteins are combinations of lipids and proteins that carry cholesterol and triglycerides in the blood. Chylomicrons are lipoproteins produced by enterocytes in the gut. They carry triglycerides to the tissues after dietary consumption. Three major types of lipoproteins are made by the liver. They vary in their relative amounts of triglycerides and cholesterol:

• Very low-density lipoproteins (VLDL)
• Low-density lipoproteins (LDL or LDL-cholesterol)
• High-density lipoproteins (HDL or HDL-cholesterol)

VLDL is predominantly composed of triglycerides, whereas LDL-cholesterol and HDL-cholesterol are richer in cholesterol. Triglycerides carried by VLDL and LDL-cholesterol are mediators of atherosclerosis development. Atherosclerosis refers to the formation of fatty material, called plaques, on inner arterial walls. It can lead to coronary artery disease, myocardial infarction, ischemic stroke, and peripheral artery disease. Therefore, LDL-cholesterol is often called “bad cholesterol.” HDL-cholesterol, on the other hand, is often called “good cholesterol” because it does not contribute to atherosclerosis; in fact, it removes cholesterol from the blood (Grundy et al., 2019).

Lipid levels in the blood are monitored using a blood test called a lipid panel. A lipid panel measures LDL-cholesterol, HDL-cholesterol, and triglycerides. It also measures the total cholesterol level. In most cases, the LDL-cholesterol level on a lipid panel is calculated using the Friedewald formula, shown below (Friedewald, 1972). Note that all of the values must be measured in milligrams per deciliter (mg/dL).

$\text{LDL Cholesterol}=\text{Total Cholesterol}-\text{HDL Cholesterol}-\frac{\text{Triglygerides}}{5}$

Optimal levels of cholesterol are subject to debate and depend on individual characteristics and cardiovascular risk. However, generally accepted optimal cholesterol levels are shown in Table 21.1.

Lipid Metabolism

Fats from the diet are emulsified by bile acids, which are made in the liver and secreted by the gallbladder when food is consumed. The emulsified fats are absorbed in the small intestine and carried via chylomicrons to the tissues. Chylomicrons interact with an enzyme called lipoprotein lipase on muscle and adipose tissue, thereby facilitating the release of free fatty acids from the triglycerides. The free fatty acids can be burned by the tissues for energy or stored as fat. The remnants of chylomicrons that are left over after fatty acid delivery return to the liver. Apolipoproteins A, B, C, and E are all involved in different aspects of this pathway.

The liver also synthesizes cholesterol and triglycerides. Cholesterol is synthesized via an enzyme called HMG CoA reductase, which is a key drug target in lipid-lowering therapy. The liver then packages cholesterol and triglycerides into VLDL particles, which travel to muscle and adipose tissue. Lipoprotein lipase breaks down VLDL particles to release free fatty acids from triglycerides for energy or storage. The remnants left over from the VLDL particles are called intermediate-density lipoproteins, which can be disposed of by the liver or further broken down by lipases to form LDL particles. LDL receptors in the liver interact with LDL-cholesterol to engulf it via endocytosis and dispose of it, effectively removing it from circulation. A protein called PCSK9 interacts with the LDL receptors, leading to their degradation; this is another important drug target in lipid-lowering therapy. HDL-cholesterol also assists in removing cholesterol from the circulation.

Lipids and Coronary Artery Disease

Cholesterol has a central role in the development of coronary artery disease (CAD). CAD is characterized by plaque buildup within the coronary arteries, which can occlude blood flow to the heart muscle. The development of CAD starts with cholesterol and triglycerides, which can be deposited onto the inner walls of arteries. Cells from the immune system called macrophages engulf the cholesterol, forming foam cells and fatty streaks within the arterial wall. Over time, cells and cellular debris build up on the fatty streaks, and a fibrous cap forms to create plaques that can narrow the artery and obstruct blood flow. Rupture of the fibrous plaque can cause a thrombus, or blood clot, to form at the site, possibly resulting in complete arterial occlusion and acute myocardial infarction.

Because of this pathophysiology, hypercholesterolemia due to elevated LDL-cholesterol is an independent risk factor for heart disease. Lipid-lowering therapy that targets LDL-cholesterol is used to decrease the risk for CAD. The optimal target levels for LDL-cholesterol and specific treatment strategies recommended in national guidelines have changed over the last 15 years and continue to evolve; however, the role of LDL-cholesterol as an independent risk factor has not changed.

Although triglycerides have been implicated in the development of atherosclerosis, treatment has not resulted in positive cardiovascular outcomes. Therefore, hypertriglyceridemia is generally not treated unless it is very severe (greater than 500 mg/dL), which can put the individual at risk for pancreatitis.

HDL-cholesterol actually has a protective role against cardiovascular disease, and higher levels (Table 21.1) are considered beneficial.

In general, lifestyle changes are considered the first-line therapy to treat dyslipidemia and prevent CAD. Many therapeutic drugs are also available. These drugs are listed in Table 21.2 and are the focus of the remainder of the chapter.