Blunted feedback suppression of SREBP processing by dietary cholesterol in transgenic mice expressing sterol-resistant SCAP(D443N)

Bobby S. Korn, Lichiro Shimomura, Yuriy Bashmakov, Robert E Hammer, Jay D Horton, Joseph L Goldstein, Michael S Brown

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Feedback regulation of cholesterol biosynthesis is mediated by membrane- bound transcription factors designated sterol regulatory element-binding proteins (SREBP)-1 and -2. In sterol-deprived cultured cells, SREBPs are released from membranes by a proteolytic process that is stimulated by SREBP cleavage-activating protein (SCAP), a membrane protein containing a sterol- sensing domain. Sterols suppress SREBP cleavage by blocking the action of SCAP, thereby decreasing cholesterol synthesis. A point mutation in SCAP(D443N) causes resistance to sterol suppression. In this article, we produced transgenic mice that express mutant SCAP(D443N) in liver. In these livers the nuclear content of SREBP-1 and -2 was increased, mRNAs encoding proteins involved in uptake and synthesis of cholesterol and fatty acids were elevated, and the livers were engorged with cholesteryl esters and triglycerides enriched in monounsaturated fatty acids. When the mice were challenged with a high cholesterol diet, cleavage of SREBP-1 and -2 was reduced in wild-type livers and less so in transgenic livers. We conclude that SCAP(D443N) stimulates proteolytic processing of native SREBPs in liver and decreases the normal sterol-mediated feedback regulation of SREBP cleavage, suggesting a central role for SCAP as a sterol sensor in liver.

Original languageEnglish (US)
Pages (from-to)2050-2060
Number of pages11
JournalJournal of Clinical Investigation
Volume102
Issue number12
DOIs
StatePublished - Dec 15 1998

Keywords

  • Cholesterol
  • Fatty acids
  • SCAP
  • Sterol regulatory element-binding proteins
  • Transgenic mice

ASJC Scopus subject areas

  • Medicine(all)

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