title: Targeting arginase-II protects mice from high-fat-diet-induced hepatic steatosis through suppression of macrophage inflammation.
abstract: Nonalcoholic fatty liver disease (NAFLD) associates with obesity and type 2 diabetes. Hypoactive AMP-activated protein kinase (AMPK), hyperactive mammalian target of rapamycin (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.
authors: Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, Chemin du Musée 5, CH-1700 Fribourg, Switzerland.
authors: Chang
authors: C
authors: Liu
authors: Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, Chemin du Musée 5, CH-1700 Fribourg, Switzerland.
authors: Angana G
authors: AG
authors: Rajapakse
authors: Laboratory HFR, Hospital Fribourgeois, Chemin des Pensionnats 2, 1708 Fribourg, Switzerland.
authors: Erwin
authors: E
authors: Riedo
authors: Laboratory HFR, Hospital Fribourgeois, Chemin des Pensionnats 2, 1708 Fribourg, Switzerland.
authors: Benoit
authors: B
authors: Fellay
authors: Promed Medical Laboratory SA, Fribourg, Switzerland.
authors: Marie-Claire
authors: MC
authors: Bernhard
authors: Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, Chemin du Musée 5, CH-1700 Fribourg, Switzerland.|National Center of Competence in Research "Kidney.CH", Switzerland.
authors: Jean-Pierre
authors: JP
authors: Montani
authors: Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, Chemin du Musée 5, CH-1700 Fribourg, Switzerland.|National Center of Competence in Research "Kidney.CH", Switzerland.
authors: Zhihong
authors: Z
authors: Yang
authors: Vascular Biology, Department of Medicine, Division of Physiology, University of Fribourg, Chemin du Musée 5, CH-1700 Fribourg, Switzerland.|National Center of Competence in Research "Kidney.CH", Switzerland.
authors: Xiu-Fen
authors: XF
authors: Ming
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D059305:Diet, High-Fat; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007249:Inflammation; D015850:Interleukin-6 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000473:pathology; D015398:Signal Transduction; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014280:Triglycerides / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D005954:Glucosephosphate Dehydrogenase; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C481673:Arg2 protein, mouse; D001119:Arginase