NPC1 and NPC2 regulate cellular cholesterol homeostasis through generation of low density lipoprotein cholesterol-derived oxysterols.

摘要: Mutations in the Niemann-Pick disease genes cause lysosomal cholesterol accumulation and impaired low density lipoprotein (LDL) esterification. These findings have been attributed to a block movement from lysosomes site of sterol regulatory machinery. In this study we show that type C1 (NPC1) C2 (NPC2) mutants increased cellular cholesterol, yet they are unable suppress LDL receptor activity biosynthesis. Cholesterol overload both NPC1 NPC2 results failure tobothsuppresssterolregulatoryelement-bindingprotein-dependent gene expression promote liver X receptor-mediated responses. However, severity defect regulation homeostasis does not correlate with endoplasmic reticulum levels, but rather degree which NPC mutant fibroblasts fail appropriately generate 25-hydroxycholesterol 27-hydroxycholesterol response cholesterol. Moreover, demonstrate treatment oxysterols reduces is able correct NPC1I1061T phenotype, most prevalent genotype. Our support role for through generation cholesterol-derived important implications disease.