Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene

Research output: Contribution to journalArticle

170 Citations (Scopus)

Abstract

Site-1 protease (S1P) cleaves membrane-bound sterol regulatory element-binding proteins (SREBPs), allowing their transcription-stimulating domains to translocate to the nucleus where they activate genes governing lipid synthesis. S1P is a potential target for lipid-lowering drugs, but the effect of S1P blockade in animals is unknown. Here, we disrupt the S1P gene in mice. Homozygous germ-line disruptions of S1P were embryonically lethal. To disrupt the gene inducibly in liver, we generated mice homozygous for a floxed S1P allele and heterozygous for a transgene encoding Cre recombinase under control of the IFN-inducible MX1 promoter. When IFN was produced, 70-90% of S1P alleles in liver were inactivated, and S1P mRNA and protein were reduced. Nuclear SREBPs declined, as did mRNAs for SREBP target genes. Cholesterol and fatty acid biosynthesis in hepatocytes declined by 75%. Low density lipoprotein (LDL) receptor mRNA declined by 50%, as did the clearance of 125I-labeled LDL from plasma, but plasma cholesterol fell, suggesting that LDL production was reduced. These data raise the possibility that S1P inhibitors may be effective lipid-lowering agents, but they suggest that nearly complete inhibition will be required.

Original languageEnglish (US)
Pages (from-to)13607-13612
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number24
DOIs
StatePublished - Nov 20 2001

Fingerprint

Lipids
Liver
Sterol Regulatory Element Binding Proteins
Genes
LDL Lipoproteins
Messenger RNA
Alleles
Cholesterol
site 1 membrane-bound transcription factor peptidase
LDL Receptors
Protease Inhibitors
Transgenes
Germ Cells
Hepatocytes
Fatty Acids
Membranes
Pharmaceutical Preparations
Proteins

Keywords

  • Cholesterol
  • Fatty acids
  • Knockout mice
  • Sterol regulatory element-binding proteins

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

@article{6c2004ccacd242aa964a285fdbd49de8,
title = "Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene",
abstract = "Site-1 protease (S1P) cleaves membrane-bound sterol regulatory element-binding proteins (SREBPs), allowing their transcription-stimulating domains to translocate to the nucleus where they activate genes governing lipid synthesis. S1P is a potential target for lipid-lowering drugs, but the effect of S1P blockade in animals is unknown. Here, we disrupt the S1P gene in mice. Homozygous germ-line disruptions of S1P were embryonically lethal. To disrupt the gene inducibly in liver, we generated mice homozygous for a floxed S1P allele and heterozygous for a transgene encoding Cre recombinase under control of the IFN-inducible MX1 promoter. When IFN was produced, 70-90{\%} of S1P alleles in liver were inactivated, and S1P mRNA and protein were reduced. Nuclear SREBPs declined, as did mRNAs for SREBP target genes. Cholesterol and fatty acid biosynthesis in hepatocytes declined by 75{\%}. Low density lipoprotein (LDL) receptor mRNA declined by 50{\%}, as did the clearance of 125I-labeled LDL from plasma, but plasma cholesterol fell, suggesting that LDL production was reduced. These data raise the possibility that S1P inhibitors may be effective lipid-lowering agents, but they suggest that nearly complete inhibition will be required.",
keywords = "Cholesterol, Fatty acids, Knockout mice, Sterol regulatory element-binding proteins",
author = "Jian Yang and Goldstein, {Joseph L} and Hammer, {Robert E} and Moon, {Young Ah} and Brown, {Michael S} and Horton, {Jay D}",
year = "2001",
month = "11",
day = "20",
doi = "10.1073/pnas.201524598",
language = "English (US)",
volume = "98",
pages = "13607--13612",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "24",

}

TY - JOUR

T1 - Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene

AU - Yang, Jian

AU - Goldstein, Joseph L

AU - Hammer, Robert E

AU - Moon, Young Ah

AU - Brown, Michael S

AU - Horton, Jay D

PY - 2001/11/20

Y1 - 2001/11/20

N2 - Site-1 protease (S1P) cleaves membrane-bound sterol regulatory element-binding proteins (SREBPs), allowing their transcription-stimulating domains to translocate to the nucleus where they activate genes governing lipid synthesis. S1P is a potential target for lipid-lowering drugs, but the effect of S1P blockade in animals is unknown. Here, we disrupt the S1P gene in mice. Homozygous germ-line disruptions of S1P were embryonically lethal. To disrupt the gene inducibly in liver, we generated mice homozygous for a floxed S1P allele and heterozygous for a transgene encoding Cre recombinase under control of the IFN-inducible MX1 promoter. When IFN was produced, 70-90% of S1P alleles in liver were inactivated, and S1P mRNA and protein were reduced. Nuclear SREBPs declined, as did mRNAs for SREBP target genes. Cholesterol and fatty acid biosynthesis in hepatocytes declined by 75%. Low density lipoprotein (LDL) receptor mRNA declined by 50%, as did the clearance of 125I-labeled LDL from plasma, but plasma cholesterol fell, suggesting that LDL production was reduced. These data raise the possibility that S1P inhibitors may be effective lipid-lowering agents, but they suggest that nearly complete inhibition will be required.

AB - Site-1 protease (S1P) cleaves membrane-bound sterol regulatory element-binding proteins (SREBPs), allowing their transcription-stimulating domains to translocate to the nucleus where they activate genes governing lipid synthesis. S1P is a potential target for lipid-lowering drugs, but the effect of S1P blockade in animals is unknown. Here, we disrupt the S1P gene in mice. Homozygous germ-line disruptions of S1P were embryonically lethal. To disrupt the gene inducibly in liver, we generated mice homozygous for a floxed S1P allele and heterozygous for a transgene encoding Cre recombinase under control of the IFN-inducible MX1 promoter. When IFN was produced, 70-90% of S1P alleles in liver were inactivated, and S1P mRNA and protein were reduced. Nuclear SREBPs declined, as did mRNAs for SREBP target genes. Cholesterol and fatty acid biosynthesis in hepatocytes declined by 75%. Low density lipoprotein (LDL) receptor mRNA declined by 50%, as did the clearance of 125I-labeled LDL from plasma, but plasma cholesterol fell, suggesting that LDL production was reduced. These data raise the possibility that S1P inhibitors may be effective lipid-lowering agents, but they suggest that nearly complete inhibition will be required.

KW - Cholesterol

KW - Fatty acids

KW - Knockout mice

KW - Sterol regulatory element-binding proteins

UR - http://www.scopus.com/inward/record.url?scp=0035923514&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035923514&partnerID=8YFLogxK

U2 - 10.1073/pnas.201524598

DO - 10.1073/pnas.201524598

M3 - Article

VL - 98

SP - 13607

EP - 13612

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 - 24

ER -