Cholesterol feeding reduces nuclear forms of sterol regulatory element binding proteins in hamster liver

Iichiro Shimomura, Yuriy Bashmakov, Hitoshi Shimano, Jay D. Horton, Joseph L. Goldstein, Michael S. Brown

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

Cholesterol feeding reduces the mRNAs encoding multiple enzymes in the cholesterol biosynthetic pathway and the low density lipoprotein receptor in livers of hamsters. Here we show that cholesterol feeding also reduces the levels of the nuclear NH2-terminal domains of sterol regulatory element binding proteins (SREBPs), which activate transcription of sterol-regulated genes. We show that livers of hamsters, like those of mice and humans, predominantly produce SREBP-2 and the 1c isoform of SREBP-1. Both are produced as membrane-bound precursors that must be proteolyzed to release the transcriptionally active NH2-terminal domains. Diets containing 0.1% to 1.0% cholesterol decreased the amount of nuclear SREBP-1c without affecting the amount of the membrane precursor or its mRNA, suggesting that cholesterol inhibits the proteolytic processing of SREBP-1 in liver as it does in cultured cells. Cholesterol also appeared to reduce the proteolytic processing of SREBP-2. In addition, at high levels of dietary cholesterol the mRNA encoding SREBP-2 declined and the amount of the precursor also fell, suggesting that cholesterol accumulation also may inhibit transcription of the SREBP-2 gone. The high-cholesterol diets reduced the amount of low density lipoprotein receptor mRNA by 30% and produced a more profound 70-90% reduction in mRNAs encoding 3-hydroxy-3-methylglutaryl CoA synthase and reductase. Treatment with lovastatin and Colestipol, which increases hepatic demands for cholesterol, increased the amount of SREBP-2 mRNA as well as the precursor and nuclear forms of the protein. This treatment caused a reciprocal decline in SREBP-1c mRNA and protein. Considered together, these data suggest that SREBPs play important roles in controlling transcription of sterol-regulated genes in liver, as they do in cultured cells.

Original languageEnglish (US)
Pages (from-to)12354-12359
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number23
DOIs
StatePublished - Nov 11 1997

Fingerprint

Sterol Regulatory Element Binding Proteins
Cricetinae
Sterol Regulatory Element Binding Protein 2
Sterol Regulatory Element Binding Protein 1
Cholesterol
Liver
Messenger RNA
LDL Receptors
Sterols
Cultured Cells
Colestipol
Diet
Hydroxymethylglutaryl CoA Reductases
Dietary Cholesterol
Lovastatin
Membranes
Biosynthetic Pathways
Nuclear Proteins
Genes
Protein Isoforms

Keywords

  • 3-hydroxy-3- methylgtutaryl CoA synthase and reductase
  • Cholesterol biosynthesis
  • Low density lipoprotein receptors
  • Transcriptional regulation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

@article{4241fc8a5eb2499886368e236a6090a7,
title = "Cholesterol feeding reduces nuclear forms of sterol regulatory element binding proteins in hamster liver",
abstract = "Cholesterol feeding reduces the mRNAs encoding multiple enzymes in the cholesterol biosynthetic pathway and the low density lipoprotein receptor in livers of hamsters. Here we show that cholesterol feeding also reduces the levels of the nuclear NH2-terminal domains of sterol regulatory element binding proteins (SREBPs), which activate transcription of sterol-regulated genes. We show that livers of hamsters, like those of mice and humans, predominantly produce SREBP-2 and the 1c isoform of SREBP-1. Both are produced as membrane-bound precursors that must be proteolyzed to release the transcriptionally active NH2-terminal domains. Diets containing 0.1{\%} to 1.0{\%} cholesterol decreased the amount of nuclear SREBP-1c without affecting the amount of the membrane precursor or its mRNA, suggesting that cholesterol inhibits the proteolytic processing of SREBP-1 in liver as it does in cultured cells. Cholesterol also appeared to reduce the proteolytic processing of SREBP-2. In addition, at high levels of dietary cholesterol the mRNA encoding SREBP-2 declined and the amount of the precursor also fell, suggesting that cholesterol accumulation also may inhibit transcription of the SREBP-2 gone. The high-cholesterol diets reduced the amount of low density lipoprotein receptor mRNA by 30{\%} and produced a more profound 70-90{\%} reduction in mRNAs encoding 3-hydroxy-3-methylglutaryl CoA synthase and reductase. Treatment with lovastatin and Colestipol, which increases hepatic demands for cholesterol, increased the amount of SREBP-2 mRNA as well as the precursor and nuclear forms of the protein. This treatment caused a reciprocal decline in SREBP-1c mRNA and protein. Considered together, these data suggest that SREBPs play important roles in controlling transcription of sterol-regulated genes in liver, as they do in cultured cells.",
keywords = "3-hydroxy-3- methylgtutaryl CoA synthase and reductase, Cholesterol biosynthesis, Low density lipoprotein receptors, Transcriptional regulation",
author = "Iichiro Shimomura and Yuriy Bashmakov and Hitoshi Shimano and Horton, {Jay D.} and Goldstein, {Joseph L.} and Brown, {Michael S.}",
year = "1997",
month = "11",
day = "11",
doi = "10.1073/pnas.94.23.12354",
language = "English (US)",
volume = "94",
pages = "12354--12359",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "23",

}

TY - JOUR

T1 - Cholesterol feeding reduces nuclear forms of sterol regulatory element binding proteins in hamster liver

AU - Shimomura, Iichiro

AU - Bashmakov, Yuriy

AU - Shimano, Hitoshi

AU - Horton, Jay D.

AU - Goldstein, Joseph L.

AU - Brown, Michael S.

PY - 1997/11/11

Y1 - 1997/11/11

N2 - Cholesterol feeding reduces the mRNAs encoding multiple enzymes in the cholesterol biosynthetic pathway and the low density lipoprotein receptor in livers of hamsters. Here we show that cholesterol feeding also reduces the levels of the nuclear NH2-terminal domains of sterol regulatory element binding proteins (SREBPs), which activate transcription of sterol-regulated genes. We show that livers of hamsters, like those of mice and humans, predominantly produce SREBP-2 and the 1c isoform of SREBP-1. Both are produced as membrane-bound precursors that must be proteolyzed to release the transcriptionally active NH2-terminal domains. Diets containing 0.1% to 1.0% cholesterol decreased the amount of nuclear SREBP-1c without affecting the amount of the membrane precursor or its mRNA, suggesting that cholesterol inhibits the proteolytic processing of SREBP-1 in liver as it does in cultured cells. Cholesterol also appeared to reduce the proteolytic processing of SREBP-2. In addition, at high levels of dietary cholesterol the mRNA encoding SREBP-2 declined and the amount of the precursor also fell, suggesting that cholesterol accumulation also may inhibit transcription of the SREBP-2 gone. The high-cholesterol diets reduced the amount of low density lipoprotein receptor mRNA by 30% and produced a more profound 70-90% reduction in mRNAs encoding 3-hydroxy-3-methylglutaryl CoA synthase and reductase. Treatment with lovastatin and Colestipol, which increases hepatic demands for cholesterol, increased the amount of SREBP-2 mRNA as well as the precursor and nuclear forms of the protein. This treatment caused a reciprocal decline in SREBP-1c mRNA and protein. Considered together, these data suggest that SREBPs play important roles in controlling transcription of sterol-regulated genes in liver, as they do in cultured cells.

AB - Cholesterol feeding reduces the mRNAs encoding multiple enzymes in the cholesterol biosynthetic pathway and the low density lipoprotein receptor in livers of hamsters. Here we show that cholesterol feeding also reduces the levels of the nuclear NH2-terminal domains of sterol regulatory element binding proteins (SREBPs), which activate transcription of sterol-regulated genes. We show that livers of hamsters, like those of mice and humans, predominantly produce SREBP-2 and the 1c isoform of SREBP-1. Both are produced as membrane-bound precursors that must be proteolyzed to release the transcriptionally active NH2-terminal domains. Diets containing 0.1% to 1.0% cholesterol decreased the amount of nuclear SREBP-1c without affecting the amount of the membrane precursor or its mRNA, suggesting that cholesterol inhibits the proteolytic processing of SREBP-1 in liver as it does in cultured cells. Cholesterol also appeared to reduce the proteolytic processing of SREBP-2. In addition, at high levels of dietary cholesterol the mRNA encoding SREBP-2 declined and the amount of the precursor also fell, suggesting that cholesterol accumulation also may inhibit transcription of the SREBP-2 gone. The high-cholesterol diets reduced the amount of low density lipoprotein receptor mRNA by 30% and produced a more profound 70-90% reduction in mRNAs encoding 3-hydroxy-3-methylglutaryl CoA synthase and reductase. Treatment with lovastatin and Colestipol, which increases hepatic demands for cholesterol, increased the amount of SREBP-2 mRNA as well as the precursor and nuclear forms of the protein. This treatment caused a reciprocal decline in SREBP-1c mRNA and protein. Considered together, these data suggest that SREBPs play important roles in controlling transcription of sterol-regulated genes in liver, as they do in cultured cells.

KW - 3-hydroxy-3- methylgtutaryl CoA synthase and reductase

KW - Cholesterol biosynthesis

KW - Low density lipoprotein receptors

KW - Transcriptional regulation

UR - http://www.scopus.com/inward/record.url?scp=0030782416&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030782416&partnerID=8YFLogxK

U2 - 10.1073/pnas.94.23.12354

DO - 10.1073/pnas.94.23.12354

M3 - Article

VL - 94

SP - 12354

EP - 12359

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 23

ER -