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

Chang Liu,Angana G Rajapakse,Marie-Claire Bernhard,Erwin Riedo,Jean-Pierre Montani,Zhihong Yang,Benoit Fellay,Xiu-Fen Ming

doi:10.1038/srep20405

Chang Liu, Angana G Rajapakse + Show 6 more

Open Access

https://doi.org/10.1038/srep20405

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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.

Highlights

To insulin resistance, type 2 diabetes and NAFLD14–17
We demonstrate that Arg-II deficiency protects against obesity-associated Nonalcoholic fatty liver disease (NAFLD) in mice through suppression of liver macrophage-mediated pro-inflammatory responses resulting in improved AMPK activation and decreased lipogenesis in hepatocytes
Pretreatment of Bone marrow-derived macrophages (BMM)-conditioned medium (CM) with neutralizing antibodies against both cytokines further reduced the expression levels of SREBP-1c and stearoyl-CoA desaturase-1 (SCD-1) (Fig. 8B,C). We provide both in vitro and in vivo evidences that Arg-II plays a role in high fat diet (HFD)-induced liver steatosis through promoting macrophage inflammation in liver

Summary

Introduction

Recent studies provide convincing evidence that resident macrophages in the liver, i.e., Kupffer cells, are activated towards M1 phenotype in obesity[18]. Pro-inflammatory macrophages are recruited to the liver under high fat diet (HFD) feeding[19,20] These studies demonstrate that both activated M1 Kupffer cells and recruited macrophages in the liver cause hepatic inflammation and promote hepatic steatosis. Our recent study provides evidence demonstrating that Arg-II promotes macrophage pro-inflammatory responses, contributing to atherogenesis and obesity-associated insulin resistance[26]. We demonstrate that Arg-II deficiency protects against obesity-associated NAFLD in mice through suppression of liver macrophage-mediated pro-inflammatory responses resulting in improved AMPK activation and decreased lipogenesis in hepatocytes

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