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Papers In Press, published online ahead of print July 1, 2008
J. Lipid Res., doi:10.1194/jlr.M800061-JLR200

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Journal of Lipid Research, Vol. 49, 1519-1528, July 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Regulation of lipin-1 gene expression by glucocorticoids during adipogenesis^*,

Peixiang Zhang^*, Lauren O'Loughlin^*, David N. Brindley and Karen Reue^1,*

^* Departments of Human Genetics and Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095
Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

^* These studies were supported by National Institutes of Health Grant HL-28481 (K.R.) and by the Canadian Institutes of Health Research (MOP 81137) and the Canadian Heart and Stroke Foundation (D.N.B.).

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of two tables and two figures.

Published, JLR Papers in Press, March 24, 2008.

¹ To whom correspondence should be addressed. e-mail: reuek{at}ucla.edu

Lipin-1 deficiency in the mouse causes generalized lipodystrophy, characterized by impaired adipose tissue development and insulin resistance. Lipin-1 expression in differentiating preadipocytes is required for normal expression of adipogenic transcription factors, including peroxisome proliferator-activated receptor and CCAAT enhancer binding protein , and for the synthesis of triacylglycerol. The requirement of lipin-1 for adipocyte differentiation can be explained, in part, by its activity as the sole adipocyte phosphatidic acid phosphatase-1 enzyme, which converts phosphatidate to diacylglycerol, the immediate precursor of triacylglycerol. Here we identify glucocorticoids as the stimulus for the induction of lipin-1 expression in differentiating adipocytes, and characterize a glucocorticoid response element (GRE) in the Lpin1 promoter. The Lpin1 GRE binds to the glucocorticoid receptor and leads to transcriptional activation in adipocytes and hepatocytes, as demonstrated by reporter gene transcription, electrophoretic mobility shift, and chromatin immunoprecipitation assays. This represents the first gene regulatory element identified to directly influence lipin-1 expression levels, and may modulate lipin-1 mRNA levels in adipose tissue and liver in conditions associated with increased local glucocorticoid concentrations in vivo, such as obesity and fasting.

Supplementary key words adipocyte differentiation • triacylglycerol • phosphatidate phosphatase

Abbreviations: AGPAT2, acylglycerolphosphate acyltransferase 2; ChIP, chromatin immunoprecipitation; CHX, cycloheximide; DEX, dexamethasone; DGAT1, diacylglycerol acyltransferase 1; EMSA, electrophoretic mobility shift assay; GPAT, glycerol 3-phosphate acyltransferase; GR, glucocorticoid receptor; GRE, glucocorticoid response element; MIX, 3-isobutyl-L-methylxanthine; PAP1, phosphatidic acid phosphatase-1; PPAR, peroxisome proliferator-activated receptor ; RACE, rapid amplification of cDNA ends; TZD, thiazolidinedione

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