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The role of cytochrome P450 in the regulation of cholesterol biosynthesis

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Lipids

Abstract

A ubiquitously expressed member of the cytochrome P450 superfamily, CYP51, encodes lanosterol 14α-demethylase, the first step in the conversion of lanosterol into cholesterol in mammals. The biosynthetic intermediates of lanosterol 14α-demethylation are oxysterols, which inhibit HMG-CoA reductase and sterol synthesis in mammalian cells in vitro. These oxysterols (5α-lanos-8-en-3β,32-diol and 3β-hydroxy-5α-lanost-8-en-32-al) are efficiently converted into cholesterol in vitro and are generally considered to be natural cholesterol precursors. When added to hepatocytes in high concentrations, besides their conversion into cholesterol, they are also rapidly metabolized into more polar sterols and into steryl esters. The 15α- and 15β-hydroxy epimers of 5α-lanost-8-en-3β-ol are also rapidly metabolized into more polar sterols and steryl esters but are not converted efficiently into cholesterol. Polar sterol formation from all these oxysterols is dependent on an active form of cytochrome P450. Oxysterols are potent regulators of the activities of transcription factors of the sterol regulatory element-binding protein family and of liver X-receptor α. It is proposed that the rapid, cytochrome P450-dependent metabolism of naturally occurring regulatory oxysterols provides a route for their deactivation so that they become incapable of affecting gene transcription. Inhibition of cytochrome P450 by the drug ketoconazole prevents the inactivation of such oxysterols, leading to a prolonged suppression of hepatic HMG-CoA reductase in vivo and in vitro.

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Abbreviations

lanosterol:

5α-lanosta-8,24-dien-3β-ol

LXRα:

liver Xreceptor alpha

SREBP:

sterol regulatory element-binding protein

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  1. Metabolic Research Laboratory, Nuffield Department of Clinical Medicine, University of Oxford, 0X2 6HE, Oxford, UK

    Geoffrey F. Gibbons

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  1. Geoffrey F. Gibbons
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Correspondence to Geoffrey F. Gibbons.

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Gibbons, G.F. The role of cytochrome P450 in the regulation of cholesterol biosynthesis. Lipids 37, 1163–1170 (2002). https://doi.org/10.1007/s11745-002-1016-x

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  • DOI: https://doi.org/10.1007/s11745-002-1016-x

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