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Peroxisome Proliferator-Activated Receptor- Transcriptionally Up-Regulates Hormone-Sensitive Lipase via the Involvement of Specificity Protein-1

Department of Biological Science and Biotechnology (T.D., J.C.), Tsinghua University, Beijing 100084, China; Chipscreen Biosciences Ltd. (T.D., S.S., X.-P.L., J.C., Z.-Q.N.), Shenzhen Research Institute of Tsinghua University, Shenzhen 518057, China; and Institute of Materia Medica (P.-P.L., Z.-F.S.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

Address all correspondence and requests for reprints to: Zhi-Qiang Ning, Chipscreen Biosciences Ltd., Shenzhen Research Institute of Tsinghua University, Nanshan District, Shenzhen 518057, China. E-mail: zqning{at}chipscreen.com.

Both peroxisome proliferator-activated receptor (PPAR)- and hormone-sensitive lipase (HSL) play important roles in lipid metabolism and insulin sensitivity. We demonstrate that expression of the HSL gene is up-regulated by PPAR and PPAR agonists (rosiglitazone and pioglitazone) in the cultured hepatic cells and differentiating preadipocytes. Rosiglitazone treatment also results in up-regulation of the HSL gene in liver and skeleton muscle from an experimental obese rat model, accompanied by the decreased triglyceride content in these tissues. The proximal promoter (–87 bp of the human HSL gene) was found to be essential for PPAR-mediated transactivating activity. This important promoter region contains two GC-boxes and binds the transcription factor specificity protein-1 (Sp1) but not PPAR. The Sp1-promoter binding activity can be endogenously enhanced by PPAR and rosiglitazone, as demonstrated by analysis of EMSA and chromatin immunoprecipitation assay. Mutations in the GC-box sequences reduce the promoter binding activity of Sp1 and the transactivating activity of PPAR. In addition, mithramycin A, the specific inhibitor for Sp1-DNA binding activity, abolishes the PPAR-mediated up-regulation of HSL. These results indicate that PPAR positively regulates the HSL gene expression, and up-regulation of HSL by PPAR requires the involvement of Sp1. Taken together, this study suggests that HSL may be a newly identified PPAR target gene, and up-regulation of HSL may be an important mechanism involved in action of PPAR agonists in type 2 diabetes.

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