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

• Published in: Endocrinology (Philadelphia) 2006-02, Vol.147 (2), p.875-884
• Main Authors: Deng, Tuo, Shan, Song, Li, Ping-Ping, Shen, Zhu-Fang, Lu, Xian-Ping, Cheng, Jing, Ning, Zhi-Qiang
• Format: Article
• Language: English
• Subjects: Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - metabolism; Agonists; Animals; Binding; Cell differentiation; Cell Line; Cell Line, Tumor; Chromatin; Diabetes mellitus (non-insulin dependent); Gene expression; Gene sequencing; Hepatocytes; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Hypoglycemic Agents - pharmacology; Immunoprecipitation; Lipase; Lipid metabolism; Lipids; Liver - cytology; Male; Nucleotide sequence; Peroxisome proliferator-activated receptors; Pioglitazone; PPAR gamma - agonists; PPAR gamma - metabolism; Preadipocytes; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - physiology; Proteins; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors; Rosiglitazone; Sp1 protein; Sp1 Transcription Factor - physiology; Statistics, Nonparametric; Stem Cells - drug effects; Stem Cells - metabolism; Sterol Esterase - genetics; Sterol Esterase - metabolism; Thiazolidinediones - pharmacology; Transcriptional Activation - physiology; Triglycerides; Up-Regulation
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2005-0623

Both peroxisome proliferator-activated receptor (PPAR)-γ 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 PPARγ and PPARγ 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 PPARγ-mediated transactivating activity. This important promoter region contains two GC-boxes and binds the transcription factor specificity protein-1 (Sp1) but not PPARγ. The Sp1-promoter binding activity can be endogenously enhanced by PPARγ 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 PPARγ. In addition, mithramycin A, the specific inhibitor for Sp1-DNA binding activity, abolishes the PPARγ-mediated up-regulation of HSL. These results indicate that PPARγ positively regulates the HSL gene expression, and up-regulation of HSL by PPARγ requires the involvement of Sp1. Taken together, this study suggests that HSL may be a newly identified PPARγ target gene, and up-regulation of HSL may be an important mechanism involved in action of PPARγ agonists in type 2 diabetes.