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  • Elevated plasma levels of low-density lipoprotein cholesterol, non–high-density lipoprotein cholesterol, lipoprotein(a), and apolipoprotein (apo) B-100.

  • Reduced plasma levels of high-density lipoprotein and apo A-I.

  • Elevated plasma levels of triglycerides.

  • Skin xanthomas.

General Considerations

Multiple epidemiologic studies have demonstrated the relationship between cardiovascular mortality and elevated plasma cholesterol levels. Lipid-lowering therapy, particularly with hydroxymethylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins), has demonstrated survival benefit in both primary prevention (patients without evidence of atherosclerotic cardiovascular disease [ASCVD]) and secondary prevention (patients with evidence of ASCVD). As a result, screening, risk stratifying, and treating dyslipidemia have become integral parts of preventive cardiovascular medicine.

A. Lipoproteins and Apolipoproteins

Cholesterol, cholesteryl esters, and triglycerides are the major lipids found in plasma. Cholesterol is an integral component of the cell membrane. It also serves a role in steroid hormone and bile acid synthesis. Triglycerides consist of fatty acid chains and phospholipids. Fatty acid chains are a primary source of energy in humans; phospholipids are key elements of all cell membranes. Cholesterol and triglycerides are insoluble in water and are transported in plasma by lipoproteins, classified as high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol, intermediate-density lipoprotein (IDL) cholesterol, and chylomicrons. Lipoproteins consist of a lipid core and a water-soluble phospholipid outer layer that carry apolipoproteins, which are specific proteins that serve as coenzymes, receptor ligands, or regulators of lipoprotein metabolism. Apolipoprotein (apo) A-I is present in HDL and promotes cholesterol efflux from tissues. Apo B, present as either apo B-100 (VLDL, IDL, LDL) or apo B-48 (chylomicron), serves as the LDL receptor ligand. Apo C-I, apo C-II, and apo C-III participate in triglyceride metabolism, and apo E is present on chylomicrons.

Lipoprotein(a) [Lp(a)] highly correlates with cardiovascular disease (CVD) and consists of an LDL particle and a specific apolipoprotein A. The structure of Lp(a) is similar to plasminogen and is thought to increase thrombogenesis. It is known to predict early atherosclerotic risk independent of other risk factors. Figure 1–1 illustrates the classes of lipoproteins and their characteristics.

Figure 1–1.

Lipoprotein characteristics. HDL, high-density lipoproteins; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; VLDL, very-low-density lipoproteins.

B. Metabolism

Transportation of dietary lipids to peripheral tissues and the liver is known as the exogenous metabolic pathway. Here, triglycerides are hydrolyzed by pancreatic lipases and are emulsified by bile acids, leading to micelle formation. Micelle uptake occurs in the intestinal brush border where fatty acids are re-esterified and packaged together with apo B-48, phospholipids, and cholesterol to form chylomicrons. Chylomicrons then reach the portal circulation where they are hydrolyzed to release fatty acids by lipoprotein lipase (LPL). LPL activity is regulated through apo C-II, which activates LPL, and apo C-III, which inhibits LPL. The free fatty acids are ...

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