Lipoprotein Metabolism

Abstract

Metabolic studies of lipoproteins have yielded important insights into regulation of energy distribution as well as providing fundamental understanding of cardiovascular risk properties of different lipoproteins. Although many factors on the molecular level have the potential to impact metabolic regulation of lipids, metabolic studies provide valuable information from a comprehensive regulatory viewpoint. With increasing emphasis on lipoprotein subfractions and their roles in promoting or protecting from cardiovascular risk, the focus of metabolic studies is largely moving toward more detailed understanding of lipoprotein subclass and individual apolipoprotein properties. See page 1370The atherogenic and antiatherogenic roles of LDL and HDL cholesterol, respectively, are well established and, by now, part of the general public knowledge. However, hereditary diseases of lipoprotein metabolism with dramatically different LDL and/or HDL cholesterol levels offer great promise to further investigate this complex system, and we have already gained considerable insight from such studies. Thus, it is well known that some hereditary conditions result in phenotypes with unusual LDL and HDL compositions. Thus, carriers of apoA-I Milano appear protected from cardiovascular disease in spite of low HDL cholesterol levels. 1,2 In another hereditary condition, lecithin:cholesterol acyltransferase (LCAT) deficiency, HDL metabolism is severely affected, and carriers of this deficiency have low levels of both HDL and LDL cholesterol with the accumulation of an aberrant lipoprotein, Lp-X. 3,4 However, in spite of low HDL cholesterol levels, cardiovascular disease is not common among LCAT-deficient subjects. 5,6 LCAT is critical for esterification of cholesterol, and in the absence of this enzyme HDL maturation is affected, resulting in small discoidal HDL particles which are thought to be deficient in promoting reverse cholesterol transport. 7 On the other hand, LDL particles are also affected by the deficiency in cholesterol esterification and have higher relative amounts of phospholipids, triglyceride, and cholesterol. 8,9 The physicochemical changes in lipoprotein properties observed in LCAT deficiency are likely to be associated with significant metabolic aberrations. Thus, the relative lack of cholesteryl esters in LDL could result in an LDL fraction with reduced atherogenicity, which might contribute to the apparent lack of CAD in these patients. The relative triglyceride enrichment of LDL under these conditions might further make LDL a better substrate for lipase activity, which could contribute to a reduction in LDL plasma circulation time. In a study of 2 LCAT-deficient patients and 17 normal subjects, Nishiwaki et al report on the metabolic basis for the complex changes in LDL properties in LCAT-deficiency in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology. 10 As expected, the LCAT-deficient subjects had very low HDL cholesterol levels and also lower apoA-I, apoB, and LDL cholesterol levels than the norma...