Dietary cholesterol, cholesterol absorption, postprandial lipemia and atherosclerosis

Abstract

The relationship among dietary cholesterol, cholesterol absorption, the metabolism of cholesterol-rich chylomicron remnants and atherosclerosis is complex; however, recent advances have provided insight into the mechanisms involved. Although dietary cholesterol is an independent risk factor for atherosclerosis, the attributable risk is low compared with dietary variables such as the amount and type of fat. Clinical studies have demonstrated that in humans consuming a typical Western-type diet, decreasing the amount of dietary cholesterol intake results in only small changes in low-density lipoprotein (LDL)-cholesterol and little or no change in the ratio of total cholesterol to high-density lipoprotein cholesterol. These findings are better appreciated when all sources of cholesterol entering the intestinal lumen are considered. Only a third of intestinal cholesterol per day is derived from the diet. Cholesterol from endogenous sources, including the bile and intestinal epithelial cells, represents the majority of cholesterol absorbed and subsequently formed into chylomicrons and secreted into the circulation. There is increasing evidence that postprandial lipoproteins are atherogenic, in particular, cholesterol-rich chylomicron remnants. These lipoproteins have the capacity to enter the arterial wall and promote atherogenesis at several stages of development, including the induction of smooth muscle cells and macrophage foam cell formation. Furthermore, enhanced delivery of chylomicron remnants to the liver decreases hepatic LDL-receptor expression, resulting in increased plasma LDL concentrations. Therefore, the inhibition of cholesterol absorption has become an attractive therapeutic target. There is growing genetic and biochemical evidence that intestinal cholesterol absorption is carrier-mediated, which has facilitated the development and characterization of small molecule inhibitors of this process. Ezetimibe, the first of these new compounds, inhibits intestinal absorption of dietary and biliary cholesterol and lowers total and LDL-cholesterol concentrations in plasma. By inhibiting cholesterol absorption, and possibly by reducing the cholesterol content of chylomicrons, ezetimibe may decrease the atherogenic potential of chylomicron remnants.