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

Laura A Navarro; Alexander Wree; Davide Povero; Michael P Berk; Akiko Eguchi; Sudakshina Ghosh; Bettina G Papouchado; Serpil C Erzurum; Ariel E Feldstein

doi:10.1016/j.jhep.2014.09.015

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

J Hepatol. 2015 Feb;62(2):412-20. doi: 10.1016/j.jhep.2014.09.015. Epub 2014 Sep 16.

Authors

Laura A Navarro¹, Alexander Wree², Davide Povero², Michael P Berk³, Akiko Eguchi², Sudakshina Ghosh⁴, Bettina G Papouchado⁵, Serpil C Erzurum⁴, Ariel E Feldstein⁶

Affiliations

¹ Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
² Department of Pediatrics, University of California San Diego (UCSD), CA, USA.
³ Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
⁴ Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
⁵ Department of Pathology, University of California San Diego, La Jolla, CA, USA.
⁶ Department of Pediatrics, University of California San Diego (UCSD), CA, USA. Electronic address: afeldstein@ucsd.edu.

Abstract

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.

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

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Arginase / metabolism*
Disease Models, Animal
Fatty Liver / etiology
Fatty Liver / immunology*
Fatty Liver / metabolism
Hyperargininemia / complications*
Hyperargininemia / immunology
Hyperargininemia / metabolism
Immunity, Innate*
Immunoblotting
Kupffer Cells / immunology*
Kupffer Cells / metabolism
Lipid Metabolism*
Lipogenesis / immunology*
Liver / metabolism
Liver / pathology
Male
Mice
Mice, Inbred C57BL

Substances

Arg2 protein, mouse
Arginase

Abstract

Publication types

MeSH terms

Substances

Grants and funding