ABSTRACT
The study of diseases of cholesterol metabolism (i.e., familial hypercholesteremia, cholesterol ester storage disease (Wolman’s disease), Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease) has provided valuable insight into mechanisms of cholesterol (lipoprotein) uptake, biosynthesis and storage, and intracellular trafficking. Molecular genetic studies of these diseases identified keys genes and led to a greater understanding of how the proteins they encode govern cholesterol dynamics. The discovery of steroidogenic acute regulatory protein (StAR) through the careful and persistent pursuit of laboratory investigation and the recognition that mutations in the StAR gene cause the rare disease of steroidogenesis, congenital lipoid adrenal hyperplasia, solved a longstanding enigma in the regulation of steroidogenesis: the identity of the “labile” protein required for cholesterol movement from the outer membrane to the inner mitochondrial membrane. The current knowledge of cellular cholesterol dynamics is reviewed, emphasizing lessons learned from the study of human diseases affecting cholesterol metabolism, with particular emphasis on the rate limiting step of steroidogenesis, the delivery of cholesterol to the inner mitochondrial membrane, which is stimulated by StAR.
