Reverse Cholesterol Transport by HDL Good Cholesterol Protects Against Atherosclerosis

Epidemiological evidence indicates that the concentration of HDL cholesterol in the plasma is inversely correlated with the risk for atherosclerosis and cardiovascular disease. Furthermore, transgenic overexpression of apolipoprotein A-I,

acids, phospholipids)

▲ FIGURE 18-22 HDL-mediated reverse cholesterol transport. Cholesterol from peripheral tissues is transferred to circulating HDL by ABCA1 (1) and possibly other transporters such as SR-BI and is converted into cholesteryl esters by the plasma enzyme LCAT. Cholesteryl esters in the HDL core can be transferred to other lipoproteins by CETP (2) for subsequent endocytosis by lipoprotein receptors expressed primarily by liver the major apolipoprotein in HDL, suppresses atherosclerosis in animal models of the disease. Several properties of HDL could contribute to its apparent ability to protect against atherosclerosis.

As discussed earlier, HDL can remove cholesterol from cells in extrahepatic tissues, including artery walls, and eventually deliver the cholesterol to the liver either directly by selective lipid uptake mediated by the receptor SR-BI or indirectly by transferring its cholesterol to other lipoproteins that are ligands of hepatic endocytic receptors (see Figure 18-13c). The excess cholesterol can then be secreted into the bile and eventually excreted from the body (see Figure 18-11). Figure 18-22 summarizes this process, called reverse cholesterol transport, which lowers both the intracellular cholesterol in macrophages and the total amount of cholesterol carried by the body, thereby directly and indirectly reducing foam cell formation. In a sense, there is a competition between LDL-mediated delivery of cholesterol to cells in the artery wall and HDL-mediated removal of excess cholesterol from those cells. In fact, the ratio of plasma LDL cholesterol to HDL cholesterol is considered a much better indicator of risk for cardiovascular disease than the total plasma cholesterol concentration.

In addition to its role in atheroprotective reverse cholesterol transport, HDL itself and some plasma enzymes associated with HDL can suppress the oxidation of LDL. Decreased LDL oxidation presumably reduces the substrates for scavenger receptors on macrophages, thereby inhibiting their accumulation of LDL cholesterol and thus foam cell formation. HDL also appears to have anti-inflammatory properties, which may contribute to its atheroprotective effect. Finally, the interaction of HDL with the receptor SR-BI can stimulate the activity of endothelial nitric oxide (NO) synthase, leading to increased production of nitric oxide.

cells (3). Alternatively, the receptor SR-BI, which is present mostly on liver and steroidogenic tissues, can mediate the selective uptake of cholesteryl esters from HDL (4|). Cholesterol delivered to the liver and bile acids derived from it are secreted into the bile ( 5). [Adapted from A. Rigotti and M. Krieger, 1999, N. Engl. J. Med. 341:2011; see also M. Krieger, 1999, Ann. Rev. Biochem. 68:523.]

This potent atheroprotective signaling molecule can diffuse into nearby vascular smooth muscle and induce its relaxation (see Figure 13-30). Relaxation of the smooth muscle around an artery results in dilation (widening) of the artery lumen and consequently increased blood flow, thereby helping to prevent ischemia and tissue damage.

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