Arginase 2 deficiency results in spontaneous steatohepatitis: A novel link between innate immune activation and hepatic de novo lipogenesis

JOURNAL OF HEPATOLOGY

卷:62

Article

Navarro, Laura A.¹  Wree, Alexander²  Povero, Davide²  Berk, Michael P.³  Eguchi, Akiko²  Ghosh, Sudakshina⁴  Papouchado, Bettina G.⁵  Erzurum, Serpil C.⁴  Feldstein, Ariel E.² 

[1] Univ Pittsburgh, Childrens Hosp Pittsburgh, Med Ctr, Pittsburgh, PA 15213 USA

[2] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA

[3] Cleveland Clin, Dept Cellular & Mol Med, Lerner Res Inst, Cleveland, OH 44106 USA

[4] Cleveland Clin, Dept Pathobiol, Lerner Res Inst, Cleveland, OH 44106 USA

[5] Univ Calif San Diego, Dept Pneumol, La Jolla, CA 92093 USA

关键词: Non-alcoholic fatty liver disease;    Steatohepatitis;    Arginase 2;    Macrophage activation;    Innate immunity;    Inflammation;    Liver fibrosis;   

DOI  :  10.1016/j.jhep.2014.09.015

来源: Elsevier

【 摘 要 】

Background & Aims: Innate immune activation has been postulated as a central mechanism for disease progression from hepatic steatosis to steatohepatitis in obesity-related fatty liver disease. Arginase 2 competes with inducible nitric oxide synthase (iNOS) for its substrate and the balance between these two enzymes plays a crucial role in regulating immune responses and macrophage activation. Our aim was to test the hypothesis that arginase 2 deficiency in mice favours progression from isolated hepatic steatosis, induced by high fat feeding, to steatohepatitis. Methods: Arginase 2-knockout (Arg2(-/-)) mice were studied for changes in liver histology and metabolic phenotype at baseline and after a short term course (7 week) feeding with a high fat (HFAT) diet. In additional experiments, Arg2 (/) mice received tail vein injections of liposome-encapsulated clodronate (CLOD) over a three-week period to selectively deplete liver macrophages. Results: Unexpectedly, Arg2(-/-) mice showed profound changes in their livers at baseline, characterized by significant steatosis as demonstrated with histological and biochemical analysis. These changes were independent of systemic metabolic parameters and associated with marked mRNA level increases of genes involved in hepatic de novo lipogenesis. Liver injury and inflammation were present with elevated serum ALT, marked infiltration of F4/80 positive cells, and increased mRNA levels of inflammatory genes. HFAT feeding exacerbated these changes. Macrophage depletion after CLOD injection significantly attenuated lipid deposition and normalized lipogenic mRNA profile of livers from Arg2(-/-) mice. Conclusions: This study identifies arginase 2 as a novel link between innate immune responses, hepatic lipid deposition, and liver injury. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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