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The ?-catenin pathway contributes to the effects of leptin on SREBP-1c expression in rat hepatic stellate cells and liver fibrosis.

ABSTRACT:

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 Ser(9) 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.

SUBMITTER: Zhai X

PROVIDER: S-EPMC3632249 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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The β-catenin pathway contributes to the effects of leptin on SREBP-1c expression in rat hepatic stellate cells and liver fibrosis.

Zhai Xuguang X Yan Kunfeng K Fan Jiye J Niu Minghui M Zhou Qian Q Zhou Yan Y Chen Hongshan H Zhou Yajun Y

British journal of pharmacology 20130501 1

<h4>Background and purpose</h4>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 ...[more]

PMID: 23347184

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