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J. Biol. Chem., Vol. 283, Issue 23, 15628-15637, June 6, 2008

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Selective Binding of Sterol Regulatory Element-binding Protein Isoforms and Co-regulatory Proteins to Promoters for Lipid Metabolic Genes in Liver^*

From the Department of Molecular Biology and Biochemistry, School of Biological Sciences and Center for Diabetes Research and Treatment, University of California, Irvine, California 92697-3900

Mice were subjected to different dietary manipulations to selectively alter expression of hepatic sterol regulatory element-binding protein 1 (SREBP-1) or SREBP-2. mRNA levels for key target genes were measured and compared with the direct binding of SREBP-1 and -2 to the associated promoters using isoform specific antibodies in chromatin immunoprecipitation studies. A diet supplemented with Zetia (ezetimibe) and lovastatin increased and decreased nuclear SREBP-2 and SREBP-1, respectively, whereas a fasting/refeeding protocol dramatically altered SREBP-1 but had modest effects on SREBP-2 levels. Binding of both SREBP-1 and -2 increased on promoters for 3-hydroxy-3-methylglutaryl-CoA reductase, fatty-acid synthase, and squalene synthase in livers of Zetia/lovastatin-treated mice despite the decline in total SREBP-1 protein. In contrast, only SREBP-2 binding was increased for the low density lipoprotein receptor promoter. Decreased SREBP-1 binding during fasting and a dramatic increase upon refeeding indicates that the lipogenic "overshoot" for fatty-acid synthase gene expression known to occur during high carbohydrate refeeding can be attributed to a similar overshoot in SREBP-1 binding. SREBP co-regulatory protein recruitment was also increased/decreased in parallel with associated changes in SREBP binding, and there were clear distinctions for different promoters in response to the dietary manipulations. Taken together, these studies reveal that there are alternative molecular mechanisms for activating SREBP target genes in response to the different dietary challenges of Zetia/lovastatin versus fasting/refeeding. This underscores the mechanistic flexibility that has evolved at the individual gene/promoter level to maintain metabolic homeostasis in response to shifting nutritional states and environmental fluctuations.

Received for publication, January 15, 2008 , and in revised form, April 11, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant HL48044. 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.

¹ Present address: The Scripps Research Institute, La Jolla, CA 92037.

² To whom correspondence should be addressed: Dept. of Molecular Biology and Biochemistry, 3244 McGaugh Hall, UC Irvine, Irvine, CA 92697-3900. E-mail: tfosborn{at}uci.edu.

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