Liu, Chang Rajapakse, Angana G. Riedo, Erwin Fellay, Benoit Bernhard, Marie-Claire Montani, Jean-Pierre Yang, Zhihong Ming, Xiu-Fen 2016-02-05 Nonalcoholic fatty liver disease (NAFLD) associates with obesity and type 2 diabetes. Hypoactive AMP-activated protein kinase (AMPK), hyperactive <i>m</i>ammalian <i>t</i>arget <i>o</i>f <i>r</i>apamycin (mTOR) signaling, and macrophage-mediated inflammation are mechanistically linked to NAFLD. Studies investigating roles of arginase particularly the extrahepatic isoform arginase-II (Arg-II) in obesity-associated NAFLD showed contradictory results. Here we demonstrate that Arg-II^−/− mice reveal decreased hepatic steatosis, macrophage infiltration, TNF-α and IL-6 as compared to the wild type (WT) littermates fed high fat diet (HFD). A higher AMPK activation (no difference in mTOR signaling), lower levels of lipogenic transcription factor SREBP-1c and activity/expression of lipogenic enzymes were observed in the Arg-II^−/− mice liver. Moreover, release of TNF-α and IL-6 from bone marrow-derived macrophages (BMM) of Arg-II^−/− mice is decreased as compared to WT-BMM. Conditioned medium from Arg-II^−/−-BMM exhibits weaker activity to facilitate triglyceride synthesis paralleled with lower expression of SREBP-1c and SCD-1 and higher AMPK activation in hepatocytes as compared to that from WT-BMM. These effects of BMM conditioned medium can be neutralized by neutralizing antibodies against TNF-α and IL-6. Thus, Arg-II-expressing macrophages facilitate diet-induced NAFLD through TNF-α and IL-6 in obesity. application/pdf https://folia.unifr.ch/global/documents/304846 https://folia.unifr.ch/documents/304846/files/yang_tar.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1038/srep20405 info:eu-repo/semantics/openAccess License undefined Scientific Reports. - 2016, vol. 6, p. 20405 info:eu-repo/classification/udc/57 Targeting arginase-II protects mice from high-fat-diet-induced hepatic steatosis through suppression of macrophage inflammation http://purl.org/coar/resource_type/c_6501