FIGURE 35–1 Metabolism of lipoproteins of hepatic origin. The heavy arrows show the primary pathways. Nascent VLDL are secreted via the Golgi apparatus. They acquire additional apo C lipoproteins and apo E from HDL. Very-low-density lipoproteins (VLDL) are converted to VLDL remnants (IDL) by lipolysis via lipoprotein lipase in the vessels of peripheral tissues. In the process, C apolipoproteins and a portion of the apo E are given back to high-density lipoproteins (HDL). Some of the VLDL remnants are converted to LDL by further loss of triglycerides and loss of apo E. A major pathway for LDL degradation involves the endocytosis of LDL by LDL receptors in the liver and the peripheral tissues, for which apo B-100 is the ligand. Dark color denotes cholesteryl esters; light color denotes triglycerides; the asterisk denotes a functional ligand for LDL receptors; triangles indicate apo E; circles and squares represent C apolipoproteins. FFA, free fatty acid; RER, rough endoplasmic reticulum. (Adapted, with permission, from Kane J, Malloy M: Disorders of lipoproteins. In: Rosenberg RN et al [editors]: The Molecular and Genetic Basis of Neurological Disease. 2nd ed. Butterworth-Heinemann, 1997.) chylomicrons and VLDL during lipolysis. HDL also acquires cholesterol from peripheral tissues, protecting the cholesterol homeostasis of cells. Free cholesterol is chiefly exported from the cell membrane by a transporter, ABCA1, acquired by a small particle termed prebeta-1 HDL, and then esterified by lecithin:cholesterol acyltransferase (LCAT), leading to the formation of larger HDL species. Cholesterol is also exported by the ABCG1 transporter and the scavenger receptor, SR-BI, to large HDL particles. The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron remnants with the aid of cholesteryl ester transfer protein (CETP). Much of the cholesteryl ester thus transferred is ultimately delivered to the liver by endocytosis of the acceptor lipoproteins. HDL can also deliver cholesteryl esters directly to the liver via SR-BI that does not cause endocytosis of the lipoproteins. At the population level, HDL cholesterol (HDL-C) levels relate inversely to atherosclerosis risk. Among individuals, the capacity to accept exported cholesterol can vary widely at identical levels of HDL-C. The ability of peripheral tissues to export cholesterol via the transporter mechanism and the acceptor capacity of HDL are emerging as major determinants of coronary atherosclerosis.
Lipoprotein disorders are detected by measuring lipids in serum after a 10-hour fast. Risk of heart disease increases with concentrations of the atherogenic lipoproteins, is inversely related to levels of HDL-C, and is modified by other risk factors. Evidence from clinical trials suggests that an LDL cholesterol (LDL-C) level of 50-60 mg/dL is optimal for patients with coronary disease. Ideally, triglycerides should be below 120 mg/dL. Although LDL-C is still the primary target of treatment, reducing the levels of VLDL and IDL also is important. Calculation of non-HDL cholesterol provides a means of assessing levels of all the lipoproteins in the VLDL to LDL cascade. Differentiation of the disorders requires identification of the lipoproteins involved (Table 35–1). Diagnosis of a primary disorder usually requires further clinical and
TABLE 35–1 The primary hyperlipoproteinemias and their treatment.
1Single-drug therapy with marine omega-3 dietary supplement should be evaluated before drug combinations are used.