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

AutorCastaño, David; Astudillo, Alma M. ; Balsinde, Jesús ; Prieto-Lloret, Jesús; Bustos, Matilde
Palabras claveAMPK
Non-alcoholic fatty liver disease (NAFLD)
Fatty acid oxidation
Fecha de publicación2014
CitaciónJournal of Hepatology 60(5): 1017-1025 (2014)
Resumen[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 10 days 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. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Descripciónet al.
Identificadoresdoi: 10.1016/j.jhep.2013.12.012
issn: 0168-8278
e-issn: 1600-0641
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