David Castaño1, Eduardo Larequi1, Idoia Belza1, Alma M Astudillo2, Eduardo Martínez-Ansó1, Jesús Balsinde2, Josepmaria Argemi1, Tomás Aragon1, María J Moreno-Aliaga3, Jordi Muntane4, Jesús Prieto5, Matilde Bustos6. 1. Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain. 2. Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), University of Valladolid, 47003 Valladolid, Spain; CIBERDEM Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 08036 Barcelona, Spain. 3. Department of Nutrition, Food Sciences, Physiology and Toxicology, University of Navarra, 31008 Pamplona, Spain. 4. Institute of Biomedicine (IBiS), University of Sevilla, 41013 Sevilla, Spain. 5. Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain; CIBEREHD Clinic of the University of Navarra, 31008 Pamplona, Spain. Electronic address: jprieto@unav.es. 6. Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain. Electronic address: mbustos@unav.es.
Abstract
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.
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 obesemice by mechanisms involving AMPK activation. rCT-1 deserves consideration as a potential therapy for NAFLD.
Authors: Miguel López-Yoldi; Marta Fernández-Galilea; Laura M Laiglesia; Eduardo Larequi; Jesús Prieto; J Alfredo Martínez; Matilde Bustos; Maria J Moreno-Aliaga Journal: J Lipid Res Date: 2014-10-28 Impact factor: 5.922
Authors: Maria D Giraldez; David Carneros; Christoph Garbers; Stefan Rose-John; Matilde Bustos Journal: Nat Rev Gastroenterol Hepatol Date: 2021-07-01 Impact factor: 46.802