Cholesterol balance and metabolism in mice with loss of function of Niemann-Pick C protein

Type C Niemann-Pick disease is due to a mutation in Niemann-Pick C (NPC) pr otein, a putative determinant of intracellular cholesterol transport. This study quantifies cholesterol balance in vivo across all tissues in mice wit h this defect. Cholesterol balance in the heterozygous animal is normal, bu t in the homozygous mouse the whole animal cholesterol pool expands continu ously from birth, reaching 5,442 mg/kg at 7 wk. The size of this pool in ea ch organ is proportional to the rate at which each tissue clears low-densit y lipoprotein-cholesterol. Despite this expansion, however, cholesterol syn thesis is increased so that whole animal synthesis equals 180 mg.day(-1).kg (-1). Forcing additional cholesterol into the liver through the clathrin-co ated pit pathway increases the hepatic cholesterol pool in control mice, al l of which is esterified, while there is a much greater increase in this po ol in mutant mice, all of which is unesterified. These findings are consist ent with the view that there is a block in sterol movement from the lysosom e to the sites of regulation in NPC disease and have important implications for understanding the function of the NPC protein in intracellular cholest erol metabolism, in general, and in the brain, in particular.