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Molecular and Cellular Biology, September 2009, p. 4864-4872, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.00553-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Sterol Regulatory Element Binding Protein 1a Regulates Hepatic Fatty Acid Partitioning by Activating Acetyl Coenzyme A Carboxylase 2 {triangledown} ,{ddagger}

Seung-Soon Im,1,{dagger} Linda E. Hammond,1,{dagger} Leyla Yousef,1 Cherryl Nugas-Selby,1 Dong-Ju Shin,1 Young-Kyo Seo,1 Loren G. Fong,2 Stephen G. Young,2 and Timothy F. Osborne1*

Department of Molecular Biology and Biochemistry, University of California, Irvine, California,1 Departments of Medicine and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California2

Received 28 April 2009/ Returned for modification 13 May 2009/ Accepted 17 June 2009

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.

* Corresponding author. Mailing address: 3244 McGaugh Hall, University of California, Irvine, CA 92697-3900. Phone: (949) 824-2979. Fax: (949) 824-8551. E-mail: tfosborn{at}uci.edu

{triangledown} Published ahead of print on 29 June 2009.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} S.-S.I. and L.E.H. contributed equally to this study.

Molecular and Cellular Biology, September 2009, p. 4864-4872, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.00553-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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