Monogenic hypercholesterolemia: new insights in pathogenesis and treatment.

The careful clinical characterization of patients with genetic forms of severe hypercholesterolemia has played a critical role in the historic linkage of hypercholesterolemia to atherosclerosis. Elucidation of gene defects that cause severe hypercholesterolemia has provided molecular entrées into the biosynthetic and regulatory pathways that produce and eliminate cholesterol and has led to the development of potent pharmacological agents that dramatically reduce circulating levels of cholesterol. The last decade of the twentieth century culminated in the demonstration that pharmacological reductions in plasma cholesterol levels result in fewer cardiovascular events and reduce total mortality. This review will summarize recent developments in our understanding of the molecular pathogenesis and treatment of monogenic forms of severe hypercholesterolemia, and some implications that these findings have for the management of common forms of hypercholesterolemia. General overview of LDL metabolism. Cholesterol is a rigid, hydrophobic molecule that confers structural integrity to plasma membranes of vertebrate cells. Excess cellular cholesterol is esterified with fatty acids to form cholesteryl esters, which are either stored as lipid droplets in cells or packaged with other apolipoproteins to form VLDL in the liver and and chylomicrons in the intestine (Figure 1). The two major cholesterol-carrying lipoproteins in humans are LDL and HDL. Approximately 70% of circulating cholesterol is transported as LDL. LDL is formed in the circulation from VLDL (Figure 1). The triglycerides and phospholipids of circulating VLDL are hydrolyzed by lipases anchored to vascular endothelial surfaces, forming cholesterolenriched VLDL remnant particles. Approximately half of the VLDL remnants are cleared from the circulation by LDL receptor–mediated (LDLR-mediated) endocytosis in the liver, and the remainder undergoes further processing to produce LDL. Most LDL is removed from the circulation after binding to the hepatic LDLR via apoB-100. Plasma levels of LDL-cholesterol (LDL-C) are directly related to the incidence of coronary events and cardiovascular deaths. Approximately 50% of the interindividual variation in plasma levels of LDL-C is attributable to genetic variation (1). The major portion of this genetic variation is polygenic, reflecting the cumulative effects of multiple sequence variants in any given individual. A subset of patients with very high plasma LDL-C levels have monogenic forms of hypercholesterolemia, which are associated with the deposition of cholesterol in tissues, producing xanthomas and coronary atherosclerosis. The clinical features, diagnosis, and pathophysiology of the known mendelian disorders of severe hypercholesterolemia will be serially reviewed (Table 1). This will be followed by a discussion of how insights gleaned from the study of these disorders may be extended to the treatment of hypercholesterolemia in the general population.