Atherogenic lipoproteins and coronary artery disease: concepts derived from recent advances in cellular and molecular biology.

RECENT ADVANCES have contributed to our understanding of lipoproteins, their metabolism, and their involvement in atherogenesis (for review see refs. 1 to 6). In this review, attention will be focused on specific types of lipoproteins and the mechanisms whereby they may be either atherogenic or antiatherogenic. Human genetic diseases of lipid metabolism and diet-induced changes in lipoproteins have provided unique insights. Atherosclerotic lesions, as they occur in man or as induced by high-fat, high-cholesterol diets in experimental animals, share many common properties. Narrowing of the vessel lumen is characterized by the deposition of cholesterol in and around cells of the arterial wall in association with cellular proliferation and fibrosis. The cholesterol that accumulates in the arterial wall is derived from plasma lipoproteins; therefore , to understand the mechanisms involved in athero-genesis, it is important to identify the specific lipopro-teins responsible for the delivery of cholesterol to the cells and to identify the cell type responsible for the accumulation of the cholesterol. Lipid transport into and out of the vessel wall appears to be a constant and dynamic process. Disease of clinical significance develops when influx and deposition of cholesterol exceeds egress of cholesterol from the arterial wall. The hyperlipidemia that develops in the genetic diseases to be discussed, or that develops with the consumption of high levels of fat and cholesterol, accelerates the lipid deposition and upsets the balance between influx and egress. Plasma lipoproteins and their metabolism. A brief consideration of the normally occurring major plasma lipoproteins and their metabolism4 is essential for understanding the role of specific lipoproteins in ather-ogenesis. Chylomicrons are synthesized by the intestine to transport dietary triglyceride and cholesterol. As they circulate in the plasma compartment, the trig-lycerides are hydrolyzed by the action of lipoprotein lipase, resulting in the production of cholesterol-enriched chylomicron remnants. The chylomicron remnants are rapidly cleared from the plasma by the liver (figure 1, step 1), and their cholesterol converted to bile acids and excreted or used in membrane and hepat-ic lipoprotein biosynthesis. Very low-density lipopro-teins (VLDLs) are triglyceride-rich particles synthesized by the liver. As the VLDLs circulate, they are acted upon by lipases, which liberates the fatty acids for use as an energy source in various tissues, and are converted to intermediate-density lipoproteins (IDLs). The IDLs are either removed from plasma by the liver (figure 1, step 2) or are converted to low-density lipo-proteins (LDLs) by further action of the …