Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 169, Issue 1, Pages 197-212Publisher
WILEY
DOI: 10.1111/bph.12114
Keywords
beta-catenin; sterol regulatory element-binding protein-1c; glycogen synthase kinase-3b; hepatic stellate cell; leptin; liver fibrosis
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Funding
- National Science Foundation of China [30971117]
- Priority Academic Program Development of Jiangsu Higher Education Institution
- Natural Science Foundation of Jiangsu Higher Education Institutions of China [11KJB310009]
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Background and Purpose 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 -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. Experimental Approach HSCs were prepared from rats and mice. Gene expressions were analysed by real-time PCR, Western blot analysis, immunostaining and transient transfection assays. Key Results Leptin increased -catenin protein but not mRNA levels in cultured HSCs. Leptin induced phosphorylation of glycogen synthase kinase-3 at Ser9 and subsequent stabilization of -catenin protein was mediated, at least in part, by ERK and p38 MAPK pathways. The leptin-induced -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 . In a mouse model of liver injury, the -catenin pathway was shown to be involved in leptin-induced liver fibrosis. Conclusions and Implications The -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.
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