Independent regulation of sterol regulatory element-binding proteins 1 and 2 in hamster liver

Zeqi Sheng, Hideo Otani, Michael S. Brown, Joseph L. Goldstein

Research output: Contribution to journalArticlepeer-review

267 Scopus citations

Abstract

Two sterol regulatory element-binding proteins (SREBPs, designated SREBP- 1 and SREBP-2), each ≃1150 amino acids in length, are attached to membranes of the endoplasmic reticulum and nuclear envelope in human and hamster tissue culture cells. In the absence of sterols, soluble fragments of ≃470 amino acids are released from both proteins by proteolytic cleavage. The soluble fragments enter the nucleus, where they bind to sterol regulatory elements in the promoters of genes encoding the low density lipoprotein receptor and 3- hydroxy-3-methylglutaryl CoA synthase, thereby activating transcription. Proteolytic processing of both SREBPs is blocked coordinately by sterol overloading and enhanced coordinately when sterols are depleted by treatment with an inhibitor of cholesterol synthesis. In contrast to these findings in cultured cells, the current data show that SREBP-1 and -2 are not coordinately regulated in hamster liver. In untreated animals the soluble fragment of SREBP-1, but not of SREBP-2, was detected by immunoblotting of a liver nuclear extract. Depletion of sterols by treatment with a bile acid- binding resin (colestipol) and a cholesterol synthesis inhibitor (mevinolin) led to a marked increase in the nuclear form of SREBP-2 and a reciprocal decline in the nuclear form of SREBP-1. These findings suggest that SREBP-1 is responsible for basal transcription of the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl CoA synthase genes in hamster liver and that SREBP-2 is responsible for the increased transcription that follows sterol depletion with a bile acid-binding resin and a cholesterol synthesis inhibitor.

Original languageEnglish (US)
Pages (from-to)935-938
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number4
DOIs
StatePublished - Feb 14 1995

Keywords

  • 3-hydroxy-3- methylglutaryl CoA synthase
  • basic- helix-loop-helix proteins
  • low density lipoprotein receptor
  • membrane-bound transcription factors
  • proteolytic processing

ASJC Scopus subject areas

  • General

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