Discovery of a novel oxysterol, 5-cholesten-3beta, 25-diol 3-sulphate, in nuclei and mitochondria following over-expression of the gene encoding StarDI

摘要

The metabolism of cholesterol to primary bile acids occurs via two main pathways in hepatocytes1. The 'neutral' pathway is considered to be the major pathway in most species2. The highly regulated microsomal enzyme, cholesterol 7a-hydroxylase (CYP7A1), is the first and rate-limiting step of this pathway3. A possibly equally important alternative pathway, the 'acidic' pathway, is initiated by the mitochondrial enzyme, sterol 27-hydroxylase (CYP27A1). Oxysterol intermediates of the 'acidic' pathway such as 27-hydroxycholesterol have been implicated as regulators of cholesterol homeostasis4, including expression of many genes encoding enzymes involved in cholesterol biosynthesis and transport . Increased CYP27A1 activity in peripheral tissues may both down-regulate cholesterol synthesis through the SREBP pathway, and enhance the efflux of cholesterol and its elimination via LXR ; however, the in-vivo ligand is currently unknown7. Thus, characterizing endogenous oxysterols and their mechanism of action is critical for a better understanding of sterol homeostasis.