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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-? 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-? 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-? and IL-6. Thus, Arg-II-expressing macrophages facilitate diet-induced NAFLD through TNF-? and IL-6 in obesity.

SUBMITTER: Liu C 

PROVIDER: S-EPMC4742779 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Targeting arginase-II protects mice from high-fat-diet-induced hepatic steatosis through suppression of macrophage inflammation.

Liu Chang C   Rajapakse Angana G AG   Riedo Erwin E   Fellay Benoit B   Bernhard Marie-Claire MC   Montani Jean-Pierre JP   Yang Zhihong Z   Ming Xiu-Fen XF  

Scientific reports 20160205


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 steatosi  ...[more]

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