Differential regulation of rat and human CYP7A 1 by the nuclear oxysterol receptor liver X receptor-α

Bryan Goodwin, Michael A. Watson, Hwajin Kim, Ji Miao, Jongsook Kim Kemper, Steven A. Kliewer

Research output: Contribution to journalArticlepeer-review

Abstract

In rodent liver, transcription of the gene encoding cholesterol 7α-hydroxylase (CYP7A1), which catalyzes the rate-limiting step in the classic bile acid synthetic pathway, is stimulated by the liver X receptor ≈ (LXRα), a nuclear receptor for oxysterol metabolites of cholesterol. This feed-forward regulatory loop provides a mechanism for the elimination of excess cholesterol from the body. In this report, we demonstrate that in primary cultures of human hepatocytes, activation of LXRα has the opposite effect, repressing CYP7A1 expression. This repression is mediated, at least in part, through induction of the orphan nuclear receptor, short heterodimer partner (SHP), which is also induced by bile acids. We demonstrate that SHP is regulated directly by LXRα through a DNA response element that overlaps with the previously characterized bile acid response element. Our data reveal a fundamental difference in the regulation of CYP7A1 in rodent and human hepatocytes and provide evidence that different species employ distinct molecular strategies to regulate cholesterol homeostasis.

Original languageEnglish (US)
Pages (from-to)386-394
Number of pages9
JournalMolecular Endocrinology
Volume17
Issue number3
DOIs
StatePublished - Mar 1 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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