Sterol regulatory element binding protein 1a regulates hepatic fatty acid partitioning by activating acetyl coenzyme A carboxylase 2

Seung Soon Im, Linda E. Hammond, Leyla Yousef, Cherryl Nugas-Selby, Dong Ju Shin, Young Kyo Seo, Loren G. Fong, Stephen G. Young, Timothy Osborne

Research output: Contribution to journalArticle

Abstract

We generated a line of mice in which sterol regulatory element binding protein 1a (SREBP-1a) was specifically inactivated by insertional mutagenesis. Homozygous mutant mice were completely viable despite expressing SREBP-1a mRNA below 5% of normal, and there were minimal effects on expression of either SREBP-1c or -2. Microarray expression studies in liver, where SREBP-1a mRNA is 1/10 the level of the highly similar SREBP-1c, demonstrated that only a few genes were affected. The only downregulated genes directly linked to lipid metabolism were Srebf1 (which encodes SREBP-1) and Acacb (which encodes acetyl coenzyme A [acetyl-CoA] carboxylase 2 [ACC2], a critical regulator of fatty acyl-CoA partitioning between cytosol and mitochondria). ACC2 regulation is particularly important during food restriction. Similar to Acacb knockout mice, SREBP-1a-deficient mice have lower hepatic triglycerides and higher serum ketones during fasting than wild-type mice. SREBP-1a and -1c have identical DNA binding and dimerization domains; thus, the failure of the more abundant SREBP-1c to substitute for activating hepatic ACC2 must relate to more efficient recruitment of transcriptional coactivators to the more potent SREBP-1a activation domain. Our chromatin immunoprecipitation results support this hypothesis.

Original languageEnglish (US)
Pages (from-to)4864-4872
Number of pages9
JournalMolecular and Cellular Biology
Volume29
Issue number17
DOIs
StatePublished - Sep 1 2009
Externally publishedYes

Fingerprint

Sterol Regulatory Element Binding Protein 1
Acetyl-CoA Carboxylase
Fatty Acids
Liver
Acyl Coenzyme A
Messenger RNA
Chromatin Immunoprecipitation
Insertional Mutagenesis
Dimerization
Ketones
Lipid Metabolism
Knockout Mice
Cytosol
Genes
Fasting
Mitochondria
Triglycerides
Down-Regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Sterol regulatory element binding protein 1a regulates hepatic fatty acid partitioning by activating acetyl coenzyme A carboxylase 2. / Im, Seung Soon; Hammond, Linda E.; Yousef, Leyla; Nugas-Selby, Cherryl; Shin, Dong Ju; Seo, Young Kyo; Fong, Loren G.; Young, Stephen G.; Osborne, Timothy.

In: Molecular and Cellular Biology, Vol. 29, No. 17, 01.09.2009, p. 4864-4872.

Research output: Contribution to journalArticle

Im, Seung Soon ; Hammond, Linda E. ; Yousef, Leyla ; Nugas-Selby, Cherryl ; Shin, Dong Ju ; Seo, Young Kyo ; Fong, Loren G. ; Young, Stephen G. ; Osborne, Timothy. / Sterol regulatory element binding protein 1a regulates hepatic fatty acid partitioning by activating acetyl coenzyme A carboxylase 2. In: Molecular and Cellular Biology. 2009 ; Vol. 29, No. 17. pp. 4864-4872.
@article{42c73053318a4f2a8865923771adbb03,
title = "Sterol regulatory element binding protein 1a regulates hepatic fatty acid partitioning by activating acetyl coenzyme A carboxylase 2",
abstract = "We generated a line of mice in which sterol regulatory element binding protein 1a (SREBP-1a) was specifically inactivated by insertional mutagenesis. Homozygous mutant mice were completely viable despite expressing SREBP-1a mRNA below 5{\%} of normal, and there were minimal effects on expression of either SREBP-1c or -2. Microarray expression studies in liver, where SREBP-1a mRNA is 1/10 the level of the highly similar SREBP-1c, demonstrated that only a few genes were affected. The only downregulated genes directly linked to lipid metabolism were Srebf1 (which encodes SREBP-1) and Acacb (which encodes acetyl coenzyme A [acetyl-CoA] carboxylase 2 [ACC2], a critical regulator of fatty acyl-CoA partitioning between cytosol and mitochondria). ACC2 regulation is particularly important during food restriction. Similar to Acacb knockout mice, SREBP-1a-deficient mice have lower hepatic triglycerides and higher serum ketones during fasting than wild-type mice. SREBP-1a and -1c have identical DNA binding and dimerization domains; thus, the failure of the more abundant SREBP-1c to substitute for activating hepatic ACC2 must relate to more efficient recruitment of transcriptional coactivators to the more potent SREBP-1a activation domain. Our chromatin immunoprecipitation results support this hypothesis.",
author = "Im, {Seung Soon} and Hammond, {Linda E.} and Leyla Yousef and Cherryl Nugas-Selby and Shin, {Dong Ju} and Seo, {Young Kyo} and Fong, {Loren G.} and Young, {Stephen G.} and Timothy Osborne",
year = "2009",
month = "9",
day = "1",
doi = "10.1128/MCB.00553-09",
language = "English (US)",
volume = "29",
pages = "4864--4872",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "17",

}

TY - JOUR

T1 - Sterol regulatory element binding protein 1a regulates hepatic fatty acid partitioning by activating acetyl coenzyme A carboxylase 2

AU - Im, Seung Soon

AU - Hammond, Linda E.

AU - Yousef, Leyla

AU - Nugas-Selby, Cherryl

AU - Shin, Dong Ju

AU - Seo, Young Kyo

AU - Fong, Loren G.

AU - Young, Stephen G.

AU - Osborne, Timothy

PY - 2009/9/1

Y1 - 2009/9/1

N2 - We generated a line of mice in which sterol regulatory element binding protein 1a (SREBP-1a) was specifically inactivated by insertional mutagenesis. Homozygous mutant mice were completely viable despite expressing SREBP-1a mRNA below 5% of normal, and there were minimal effects on expression of either SREBP-1c or -2. Microarray expression studies in liver, where SREBP-1a mRNA is 1/10 the level of the highly similar SREBP-1c, demonstrated that only a few genes were affected. The only downregulated genes directly linked to lipid metabolism were Srebf1 (which encodes SREBP-1) and Acacb (which encodes acetyl coenzyme A [acetyl-CoA] carboxylase 2 [ACC2], a critical regulator of fatty acyl-CoA partitioning between cytosol and mitochondria). ACC2 regulation is particularly important during food restriction. Similar to Acacb knockout mice, SREBP-1a-deficient mice have lower hepatic triglycerides and higher serum ketones during fasting than wild-type mice. SREBP-1a and -1c have identical DNA binding and dimerization domains; thus, the failure of the more abundant SREBP-1c to substitute for activating hepatic ACC2 must relate to more efficient recruitment of transcriptional coactivators to the more potent SREBP-1a activation domain. Our chromatin immunoprecipitation results support this hypothesis.

AB - We generated a line of mice in which sterol regulatory element binding protein 1a (SREBP-1a) was specifically inactivated by insertional mutagenesis. Homozygous mutant mice were completely viable despite expressing SREBP-1a mRNA below 5% of normal, and there were minimal effects on expression of either SREBP-1c or -2. Microarray expression studies in liver, where SREBP-1a mRNA is 1/10 the level of the highly similar SREBP-1c, demonstrated that only a few genes were affected. The only downregulated genes directly linked to lipid metabolism were Srebf1 (which encodes SREBP-1) and Acacb (which encodes acetyl coenzyme A [acetyl-CoA] carboxylase 2 [ACC2], a critical regulator of fatty acyl-CoA partitioning between cytosol and mitochondria). ACC2 regulation is particularly important during food restriction. Similar to Acacb knockout mice, SREBP-1a-deficient mice have lower hepatic triglycerides and higher serum ketones during fasting than wild-type mice. SREBP-1a and -1c have identical DNA binding and dimerization domains; thus, the failure of the more abundant SREBP-1c to substitute for activating hepatic ACC2 must relate to more efficient recruitment of transcriptional coactivators to the more potent SREBP-1a activation domain. Our chromatin immunoprecipitation results support this hypothesis.

UR - http://www.scopus.com/inward/record.url?scp=68849091864&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68849091864&partnerID=8YFLogxK

U2 - 10.1128/MCB.00553-09

DO - 10.1128/MCB.00553-09

M3 - Article

C2 - 19564420

AN - SCOPUS:68849091864

VL - 29

SP - 4864

EP - 4872

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 17

ER -