Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXRα

Daniel J. Peet, Stephen D Turley, Wenzhen Ma, Bethany A. Janowski, Jean Marc A Lobaccaro, Robert E Hammer, David J Mangelsdorf

Research output: Contribution to journalArticlepeer-review

1140 Scopus citations

Abstract

We demonstrate that mice lacking the oxysterol receptor, LXRα, lose their ability to respond normally to dietary cholesterol and are unable to tolerate any amount of cholesterol in excess of that which they synthesize de novo. When fed diets containing cholesterol, LXRα (-/-) mice fail to induce transcription of the gene encoding cholesterol 7α-hydroxylase (Cyp7a), the rate-limiting enzyme in bile acid synthesis. This defect is associated with a rapid accumulation of large amounts of cholesterol in the liver that eventually leads to impaired hepatic function. The regulation of several other crucial lipid metabolizing genes is also altered in LXRα (-/-) mice. These results demonstrate the existence of a physiologically significant feed-forward regulatory pathway for sterol metabolism and establish the role of LXRα as the major sensor of dietary cholesterol.

Original languageEnglish (US)
Pages (from-to)693-704
Number of pages12
JournalCell
Volume93
Issue number5
DOIs
StatePublished - May 29 1998

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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