Cardiotrophin-1 eliminates hepatic steatosis in obese mice by mechanisms involving AMPK activation

Dec 24, 2013Journal of hepatology

Cardiotrophin-1 may reduce liver fat in obese mice through energy regulation pathways

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Abstract

Treatment with recombinant CT-1 for 10 days induced a marked decrease in liver triglyceride content in two NAFLD mouse models.

CT-1 levels were increased in both human and mouse fatty livers.
Administration of rCT-1 resulted in a higher proportion of poly-unsaturated fatty acids and reduced monounsaturated fatty acids in the liver.
Chronic rCT-1 treatment led to decreased expression of genes associated with fat production and import into liver cells.
Improvements in insulin signaling and reduced inflammation were observed alongside changes in liver fat composition.
The effects of rCT-1 on fat metabolism may be mediated through the activation of AMPK.

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BACKGROUND & AIMS: Cardiotrophin-1 (CT-1) is a hepatoprotective cytokine that modulates fat and glucose metabolism in muscle and adipose tissue. Here we analyzed the changes in hepatic fat stores induced by recombinant CT-1 (rCT-1) and its therapeutic potential in non-alcoholic fatty liver disease (NAFLD).

METHODS: rCT-1 was administered to two murine NAFLD models: ob/ob and high fat diet-fed mice. Livers were analyzed for lipid composition and expression of genes involved in fat metabolism. We studied the effects of rCT-1 on lipogenesis and fatty acid (FA) oxidation in liver cells and the ability of dominant negative inhibitor of AMP-activated protein kinase (AMPK) to block these effects.

RESULTS: CT-1 was found to be upregulated in human and murine steatotic livers. In two NAFLD mouse models, treatment with rCT-1 for 10days induced a marked decrease in liver triglyceride content with augmented proportion of poly-unsaturated FA and reduction of monounsaturated species. These changes were accompanied by attenuation of inflammation and improved insulin signaling. Chronic administration of rCT-1 caused downregulation of lipogenic genes and genes involved in FA import to hepatocytes together with amelioration of ER stress, elevation of NAD(+)/NADH ratio, phosphorylation of LKB1 and AMPK, increased expression and activity of sirtuin1 (SIRT1) and upregulation of genes mediating FA oxidation. rCT-1 potently inhibited de novo lipogenesis and stimulated FA oxidation in liver cells both in vitro and in vivo. In vitro studies showed that these effects are mediated by activated AMPK.

CONCLUSIONS: rCT-1 resolves hepatic steatosis in obese mice by mechanisms involving AMPK activation. rCT-1 deserves consideration as a potential therapy for NAFLD.

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Cardiotrophin-1 eliminates hepatic steatosis in obese mice by mechanisms involving AMPK activation

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