Studies on human sterol 27-hydroxylase with emphasis on its mechanism of regulation and metabolic consequences of a deficient enzyme

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Laboratory Medicine

Sammanfattning: Sterol 27-hydroxylase (CYP27A1) is a mitochondrial cytochrome P-450 enzyme present in most animal cells. In hepatocytes, CYP27A1 has an important role in connection with biosynthesis of bile acids from cholesterol. In other cells the enzyme is responsible for a mechanism by which cholesterol can be eliminated by conversion into more polar products that can easily escape from the cells. The above properties are consistent with an antiatherogenic effect of CYP27A1, which is also illustrated by the fact that patients lacking the enzyme develop premature atherosclerosis and xanthomas in tendons and in the brain (Cerebrotendinous Xanthomatosis). Upregulation of CYP27A1 would represent a new strategy to treat atherosclerosis, and thus it was regarded to be important to expand the knowledge about the mechanism of regulation of the enzyme in man. In the first part of this thesis the following findings were made, all of which are consistent with an antiatherogenic effect of CYP27A1: There was a marked induction of CYP27A1 during differentiation of human monocytes into macrophages, with increased levels of mRNA and production of 27-oxygenated products of cholesterol. This induction has the potential to counteract the effects of induction of scavenger receptors. The cytokine TGF

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