Sex-determining region Y-box 9 acts downstream of NADPH oxidase to influence the effect of leptin on PPARγ1 expression in hepatic stellate cells.
Leptin, an adipocyte-derived hormone, promotes liver fibrogenesis and inhibits the expression of peroxisome-proliferator activated receptor γ (PPARγ), a key transcription factor in inhibition of hepatic stellate cell (HSC) activation, in HSCs. This research aimed to further investigate the mechanisms underlying leptin regulation of PPARγ1 in HSCs in vivo and in vitro. Results demonstrated that sex-determining region Y-box 9 (Sox9) could bind to a site around -2275 within leptin response region of PPARγ1 promoter and inhibited PPARγ1 expression. Sox9 upregulated the expressions of α1(I)collagen and alpha-smooth muscle actin in HSCs. Leptin stimulated Sox9 expression and Sox9 binding to PPARγ1 promoter. The signaling pathways of NADPH oxidase, β-catenin, and delta-like homolog1 (DLK1) mediated leptin upregulation of Sox9 expression. Moreover, there existed crosstalk between NADPH oxidase pathway and β-catenin or DLK1 signaling pathway. Human liver specimens of cirrhosis were shown to be of a large number of the positive HSCs for p47phox (playing a central role in NADPH oxidase activity), 4-hydroxynonenal (a lipid peroxidation product), Sox9, and α-smooth muscle actin whereas PPARγ-positive HSCs were rarely detected. These results might deepen understanding of the molecular mechanisms for leptin inhibition of PPARγ1 expression in HSCs and for the liver fibrosis associated with leptin.
Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China.
Haowen
H
Qiao
Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China.
Qing
Q
Cao
The first affiliated hospital of Zhejiang university, Hangzhou 31000, Zhejiang, China.
Yucheng
Y
Fu
Department of Pharmacology, School of Pharmacy, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China.
Wei
W
Guan
Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China.
Fangyun
F
Cheng
Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China.
Juanjuan
J
Wu
Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China.
Xin
X
Jia
Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China.
Hongshan
H
Chen
Department of Biochemistry & Molecular Biology, Medical College, Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China. Electronic address: zhouyajun64@hotmail.com.
Yajun
Y
Zhou
Hepatic stellate cell; Leptin; Liver fibrosis; NADPH oxidase; Peroxisome-proliferator activated receptor γ1; Sex-determining region Y-box 9