[Low density lipoprotein receptor and hypercholesterolemia]

Familial hypercholesterolaemia is the most frequent of the monogenic genetic disorders. The studies of Brown, Goldstein and collaborators have facilitated decisive progress in our understanding of the pathophysiology of this hypercholesterolaemia, and more specifically in our knowledge of the metabolism of the low-density lipoproteins (LDL) and of cholesterol at the cellular level. Indeed, they have documented the existence of a ubiquitous receptor which facilitates cellular uptake of LDL-cholesterol; such cholesterol is subsequently available to satisfy the metabolic requirements of the cell. The description of numerous mutations of the LDL receptor protein have allowed an exemplary approach to the study of the relationship between its structure and function. Familial hypercholesterolaemia represents a classical illustration of the atherogenic role of LDL-cholesterol in a clinical context in man. This disorder has already featured three minor therapeutic revolutions: LDL apheresis, inhibitors of HMG-CoA reductase (statins) and most recently, gene therapy.