title: GATA binding protein 3 is correlated with leptin regulation of PPARγ1 in hepatic stellate cells.
abstract: Accumulating evidence reveals that hormone leptin, mainly produced by adipocyte, plays a unique role in promotion of liver fibrosis. Hepatic stellate cell (HSC) activation is a key step in liver fibrosis and peroxisome-proliferator activated receptor γ (PPARγ) exerts a crucial role in inhibition of HSC activation. Our previous researches demonstrated that leptin reduced PPARγ1 (a major subtype of PPARγ in HSCs) expression through GATA binding protein 2 (GATA2) binding to a site around -2323 in PPARγ1 promoter. The present researches aimed to examine the effect of GATA3 on leptin-induced inhibition of PPARγ1 and elucidate the relationship between GATA3 and GATA2. Gene expressions were analysed by real-time PCR, western blot, luciferase assay and immunostaining. C57BL/6J ob/ob mouse model of thioacetamide-induced liver injury was used in vivo. Results demonstrate that leptin significantly induces GATA3 expression in HSCs by multiple signalling pathways including NADPH oxidase pathway. There exist crosstalks between NADPH oxidase pathway and the other pathways. GATA3 can bind to GATA2-binding site in PPARγ1 promoter and interacts with GATA2, contributing to leptin inhibition of PPARγ1 expression in HSCs. These data demonstrated novel molecular events for leptin inhibition of PPARγ1 expression in HSCs and thus might have potential implications for clarifying the detailed mechanisms underlying liver fibrosis in diseases in which circulating leptin levels are elevated such as non-alcoholic steatohepatitis in obese patients.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guan
authors.affiliation: Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Nantong, Jiangsu, China.
authors.forename: Fangyun
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Nantong, Jiangsu, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Nantong, Jiangsu, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Nantong, Jiangsu, China.
authors.forename: Huixia
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Nantong, Jiangsu, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D057809:HEK293 Cells; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D050990:GATA3 Transcription Factor; D020738:Leptin; D047495:PPAR gamma
keywords: GATA binding protein 3; hepatic stellate cell; leptin; liver fibrosis; peroxisome-proliferator activated receptor γ1