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

• Published in: Journal of hepatology Vol. 60; no. 5; pp. 1017 - 1025
• Main Authors: Castaño, David, Larequi, Eduardo, Belza, Idoia, Astudillo, Alma M, Martínez-Ansó, Eduardo, Balsinde, Jesús, Argemi, Josepmaria, Aragon, Tomás, Moreno-Aliaga, María J, Muntane, Jordi, Prieto, Jesús, Bustos, Matilde
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2014
• Subjects: AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Cardiotrophin-1; Cytokines - genetics; Cytokines - metabolism; Cytokines - therapeutic use; Diet, High-Fat - adverse effects; Disease Models, Animal; Enzyme Activation; Fatty acid oxidation; Fatty Acids - metabolism; Gastroenterology and Hepatology; Hepatocytes - metabolism; Humans; Insulin Resistance; Lipid Metabolism; Lipogenesis; Liver - metabolism; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic fatty liver disease (NAFLD); Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Recombinant Proteins - therapeutic use; Sirtuin 1 - metabolism; Sterol Regulatory Element Binding Protein 1 - metabolism; Transcription Factors - metabolism; Up-Regulation; Fatty acid oxidation; IRS1; 2H 2O; HFD; peroxisome proliferator-activated receptor-gamma coactivator-1alpha; inositol-requiring enzyme; ALT; DN; high fat diet; CPT1; VLDL; FBS; NAMPT; adenovirus; sirtuin1; dominant negative AMPK; SCD1; Lipogenesis; MCAD; calmodulin-dependent protein kinase kinase β; medium-chain acyl-CoA dehydrogenase; rCT-1; Cardiotrophin-1; recombinant CT-1; liver kinase B; PUFA; PPARα; monounsaturated fatty acids; carbohydrate-responsive element-binding protein; CaMKKβ; ER; SIRT1; green fluorescent protein; dominant negative; fetal bovine serum; stearoyl-Coenzyme A desaturase 1; very low density lipoproteins; carnitine palmitoyltransferase 1; fatty acid synthase; AMPK; FA; diacylglycerol; non-alcoholic steatohepatitis; NAFLD; DNAMPK; non-alcoholic fatty liver disease; triacylglycerol; Ad; adiponectin receptors; MUFA; polyunsaturated fatty acids; Non-alcoholic fatty liver disease (NAFLD); fatty acid; LPL; CT-1; alanine transferase; AMP-activated protein kinase; LKB1; GFP; peroxisome proliferator-activated receptor alpha; CHREBP; IRE1; insulin receptor substrate; X-box-binding protein1; nicotinamide phosphoribosyltransferase; XBP1; AST; PGC-1α; DAG; NASH; SREBP-1c; ACC2; deuterated water; TG; adipoR; PF; sterol regulatory element binding protein 1c; lipoprotein lipase; FAS; pair fed; aspartate transaminase; acetyl CoA carboxylase 2; endoplasmic reticulum; 2H2O
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2013.12.012

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.