Unsaturated fatty acids inhibit transcription of the sterol regulatory element-binding protein-1c (SREBP-1c) gene by antagonizing ligand-dependent activation of the LXR

Jiafu Ou, Hua Tu, Bei Shan, Alvin Luk, Russell A. DeBose-Boyd, Yuriy Bashmakov, Joseph L. Goldstein, Michael S. Brown

Research output: Contribution to journalArticle

365 Scopus citations

Abstract

Sterol regulatory element-binding protein-1c (SREBP-1c) enhances transcription of genes encoding enzymes of unsaturated fatty acid biosynthesis in liver. SREBP-1c mRNA is known to increase when cells are treated with agonists of liver X receptor (LXR), a nuclear hormone receptor, and to decrease when cells are treated with unsaturated fatty acids, the end products of SREBP-1c action. Here we show that unsaturated fatty acids lower SREBP-1c mRNA levels in part by antagonizing the actions of LXR. In cultured rat hepatoma cells, arachidonic acid and other fatty acids competitively inhibited activation of the endogenous SREBP-1c gene by an LXR ligand. Arachidonate also blocked the activation of a synthetic LXR-dependent promoter in transfected human embryonic kidney-293 cells. In vitro, arachidonate and other unsaturated fatty acids competitively blocked activation of LXR, as reflected by a fluorescence polarization assay that measures ligand-dependent binding of LXR to a peptide derived from a coactivator. These data offer a potential mechanism that partially explains the long-known ability of dietary unsaturated fatty acids to decrease the synthesis and secretion of fatty acids and triglycerides in livers of humans and other animals.

Original languageEnglish (US)
Pages (from-to)6027-6032
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number11
DOIs
StatePublished - May 22 2001

Keywords

  • Arachidonic acid
  • Fatty acid synthesis
  • Nuclear receptors

ASJC Scopus subject areas

  • General

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