Regulation of Hepatic Cytochromes P450 by Lipids and Cholesterol

Mateja      Hafner; Tadeja      Rezen; Damjana      Rozman

Abstract

Cytochromes P450 of the liver are involved in maintenance of lipid homeostasis (cholesterol, vitamin D, oxysterol and bile acid metabolism) and in detoxification processes of endogenous compounds (i. e. bile acids) and xenochemicals (drugs). This review describes the roles of various CYPs in production of cholesterol related endogenous metabolites. These metabolites (oxysterols, bile acids, vitamin D3) act as activators of a battery of nuclear receptors, in particular liver X receptor (LXR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), farnesoid X receptor (FXR) and vitamin D receptor (VDR). Nuclear receptors that are activated by cholesterol metabolites or by drugs (i. e. PXR or CAR) bind to promoter regions of responsive genes. The downstream genes include CYPs from cholesterol metabolism and/or from drug metabolism whose transcription is activated in a feedback manner. Cholesterol metabolites are thus major actors of the cross-talk that is mediated by nuclear receptors and activated CYPs. This results in a simultaneous regulation of genes from cholesterol metabolism, drug metabolism and also other pathways. The interplay between metabolism of endogenous and exogenous compounds is a frequent cause of drug failures that can now be explained at the molecular level.

Keywords: Bile acids, cytochrome P450, lipids regulation, nuclear receptors, oxysterols, vitamin D, CYP27B1, CCAAT-enhancer-binding proteins, INSIG (Insulin induced gene), LRH-1(Liver receptor homologue 1)