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J. Biol. Chem., Vol. 280, Issue 7, 5258-5266, February 18, 2005

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The Gene Encoding Acyl-CoA-binding Protein Is Subject to Metabolic Regulation by Both Sterol Regulatory Element-binding Protein and Peroxisome Proliferator-activated Receptor in Hepatocytes^*

Maria B. Sandberg, Maria Bloksgaard, Daniel Duran-Sandoval, Caroline Duval, Bart Staels, and Susanne Mandrup¶

From the Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark and the Département d'Athérosclérose, Institut Pasteur de Lille and Faculté de Pharmacie, Université de Lille 2, 59019 Lille, France

The acyl-CoA-binding protein (ACBP) is a 10-kDa intracellular lipid-binding protein that transports acylCoA esters. The protein is expressed in most cell types at low levels; however, expression is particularly high in cells with a high turnover of fatty acids. Here we confirm a previous observation that ACBP expression in rodent liver is down-regulated by fasting, and we show that insulin but not glucose is the inducer of ACBP expression in primary rat hepatocytes. In keeping with the regulation by insulin, we show that ACBP is a sterol regulatory element-binding protein 1c (SREBP-1c) target gene in hepatocytes. Members of the SREBP family activate the rat ACBP gene through binding sites for SREBP and the auxiliary factors Sp1 and nuclear factor Y in the proximal promoter. In addition, we show that ACBP is a peroxisome proliferator-activated receptor (PPAR) target gene in cultured hepatocytes and is induced in the liver by fibrates in a PPAR-dependent manner. Thus, ACBP is a dual PPAR and SREBP-1c target gene in hepatocytes. Fasting leads to reduced activity of SREBP but increased activity of PPAR in hepatocytes, and in keeping with ACBP being a dual target gene, we show that ACBP expression is significantly lower in livers from PPAR knock-out mice than in livers from wild type mice. In conclusion, expression of ACBP in rodent hepatocytes is subject to dual metabolic regulation by PPAR and SREBP-1c, which may reflect the need for ACBP during lipogenic as well as lipo-oxidative conditions.

Received for publication, July 6, 2004 , and in revised form, December 14, 2004.

^* This work was supported by grants from the Danish Natural Science Research Council, the Danish Health Science Research Council (to S. M.), by FEDER-Conseil Régional Nord-Pas-de-Calais Grant Génopole 01360124, and by grants from the Fondation Leducq (to B. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark. Tel.: 45-6550-2340; Fax: 45-6550-2467; E-mail: s.mandrup{at}bmb.sdu.dk.

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