title: GATA binding protein 2 mediates leptin inhibition of PPARγ1 expression in hepatic stellate cells and contributes to hepatic stellate cell activation.
abstract: Hepatic stellate cell (HSC) activation is a crucial step in the development of liver fibrosis. Peroxisome-proliferator activated receptor γ (PPARγ) exerts a key role in the inhibition of HSC activation. Leptin reduces PPARγ expression in HSCs and plays a unique role in promoting liver fibrosis. The present studies aimed to investigate the mechanisms underlying leptin regulation of PPARγ1 (a major subtype of PPARγ) in HSCs in vivo and in vitro. Results revealed a leptin response region in mouse PPARγ1 promoter and indicated that the region included a GATA binding protein binding site around position -2323. GATA binding protein-2 (GATA-2) could bind to the site and inhibit PPARγ1 promoter activity in HSCs. Leptin induced GATA-2 expression in HSCs in vitro and in vivo. GATA-2 mediated leptin inhibition of PPARγ1 expression by its binding site in PPARγ1 promoter in HSCs and GATA-2 promoted HSC activation. Leptin upregulated GATA-2 expression through β-catenin and sonic hedgehog pathways in HSCs. Leptin-induced increase in GATA-2 was accompanied by the decrease in PPARγ expression in HSCs and by the increase in the activated HSC number and liver fibrosis in vivo. Our data might suggest a possible new explanation for the promotion effect of leptin on liver fibrogenesis.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, Qi Xiou Road 19, Nantong 226001, Jiangsu, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, Qi Xiou Road 19, Nantong 226001, Jiangsu, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guan
authors.affiliation: Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi Xiou Road 19, Nantong, 226001, Jiangsu, China.
authors.forename: Haowen
authors.initials: H
authors.lastname: Qiao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nantong University, Qi Xiou Road 19, Nantong 226001, Jiangsu, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi Xiou Road 19, Nantong, 226001, Jiangsu, China.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi Xiou Road 19, Nantong, 226001, Jiangsu, China.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Zhai
authors.affiliation: Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi Xiou Road 19, Nantong, 226001, Jiangsu, China. Electronic address: yajunzhou97127@yahoo.com.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002478:Cells, Cultured; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: D050989:GATA2 Transcription Factor; D053823:Hedgehog Proteins; D020738:Leptin; D047495:PPAR gamma; C465570:Shh protein, mouse; D051176:beta Catenin
keywords: GATA binding protein 2; Hepatic stellate cell; Leptin; Liver fibrosis; Peroxisome-proliferator activated receptor γ1