The β-catenin pathway contributes to the effects of leptin on SREBP-1c expression in rat hepatic stellate cells and liver fibrosis.
OBJECTIVE
Liver fibrosis is commonly associated with obesity and most obese patients develop hyperleptinaemia. The adipocytokine leptin has a unique role in the development of liver fibrosis. Activation of hepatic stellate cells (HSCs) is a key step in hepatic fibrogenesis and sterol regulatory element-binding protein-1c (SREBP-1c) can inhibit HSC activation. We have shown that leptin strongly inhibits SREBP-1c expression in rat HSCs. Hence, we aimed to clarify whether the β-catenin pathway, the crucial negative regulator of adipocyte differentiation, mediates the effects of leptin on SREBP-1c expression in HSCs and in mouse liver fibrosis.


METHODS
HSCs were prepared from rats and mice. Gene expressions were analysed by real-time PCR, Western blot analysis, immunostaining and transient transfection assays.


RESULTS
Leptin increased β-catenin protein but not mRNA levels in cultured HSCs. Leptin induced phosphorylation of glycogen synthase kinase-3β at Ser(9) and subsequent stabilization of β-catenin protein was mediated, at least in part, by ERK and p38 MAPK pathways. The leptin-induced β-catenin pathway reduced SREBP-1c expression and activity but did not affect protein levels of key regulators controlling SREBP-1c activity, and was not involved in leptin inhibition of liver X receptor α. In a mouse model of liver injury, the β-catenin pathway was shown to be involved in leptin-induced liver fibrosis.


CONCLUSIONS
The β-catenin pathway contributes to leptin regulation of SREBP-1c expression in HSCs and leptin-induced liver fibrosis in mice. These results have potential implications for clarifying the mechanisms of liver fibrogenesis associated with elevated leptin levels.
Department of Biochemistry and Molecular Biology, Medical College, Nantong University, Nantong, China.
Xuguang
X
Zhai
Kunfeng
K
Yan
Jiye
J
Fan
Minghui
M
Niu
Qian
Q
Zhou
Yan
Y
Zhou
Hongshan
H
Chen
Yajun
Y
Zhou
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism; D020738:Leptin / Q000008:administration & dosage / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000473:pathology*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020738:Leptin; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases