Peroxisome proliferator-activated receptor-gamma transcriptionally up-regulates hormone-sensitive lipase via the involvement of specificity protein-1.
Both peroxisome proliferator-activated receptor (PPAR)-gamma 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 PPARgamma and PPARgamma 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 PPARgamma-mediated transactivating activity. This important promoter region contains two GC-boxes and binds the transcription factor specificity protein-1 (Sp1) but not PPARgamma. The Sp1-promoter binding activity can be endogenously enhanced by PPARgamma 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 PPARgamma. In addition, mithramycin A, the specific inhibitor for Sp1-DNA binding activity, abolishes the PPARgamma-mediated up-regulation of HSL. These results indicate that PPARgamma positively regulates the HSL gene expression, and up-regulation of HSL by PPARgamma requires the involvement of Sp1. Taken together, this study suggests that HSL may be a newly identified PPARgamma target gene, and up-regulation of HSL may be an important mechanism involved in action of PPARgamma agonists in type 2 diabetes.
Deng
Tuo
T
Department of Biological Science and Biotechnology, Tsinghua University, Beijing, China.
Shan
Song
S
Li
Ping-Ping
PP
Shen
Zhu-Fang
ZF
Lu
Xian-Ping
XP
Cheng
Jing
J
Ning
Zhi-Qiang
ZQ
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008099:Liver / Q000166:cytology; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D000077205:Pioglitazone; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D000077154:Rosiglitazone; D016329:Sp1 Transcription Factor / Q000502:physiology*; D018709:Statistics, Nonparametric; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D015533:Transcriptional Activation / Q000502:physiology*; D015854:Up-Regulation
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D016329:Sp1 Transcription Factor; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D002787:Sterol Esterase; D000077205:Pioglitazone