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Submitted on May 23, 2005
Accepted on October 24, 2005
Department of Biological Science and Biotechnology, Tsinghua University, Beijing 100084; Chipscreen Biosciences Ltd., Shenzhen Research Institute of Tsinghua University, Shenzhen 518057; Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
* To whom correspondence should be addressed. 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 (TG) 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 Sp1, but not PPAR. The Sp1-promoter binding activity can be endogenously enhanced by PPAR and Rosiglitazone, as demonstrated by analysis of electrophoretic mobility shift and chromatin immunoprecipitation assays. 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.
•
thiazolidinedione •
Sp1 •
type 2 diabetes
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