title: Arginase 2 deficiency results in spontaneous steatohepatitis: a novel link between innate immune activation and hepatic de novo lipogenesis.
abstract: OBJECTIVE
  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.
authors.affiliation: Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Navarro
authors.affiliation: Department of Pediatrics, University of California San Diego (UCSD), CA, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Wree
authors.affiliation: Department of Pediatrics, University of California San Diego (UCSD), CA, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Povero
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Berk
authors.affiliation: Department of Pediatrics, University of California San Diego (UCSD), CA, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Eguchi
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Sudakshina
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Bettina G
authors.initials: BG
authors.lastname: Papouchado
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.affiliation: Department of Pediatrics, University of California San Diego (UCSD), CA, USA. Electronic address: afeldstein@ucsd.edu.
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D020162:Hyperargininemia / Q000150:complications* / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate; D015151:Immunoblotting; D007728:Kupffer Cells / Q000276:immunology* / Q000378:metabolism; D050356:Lipid Metabolism; D050155:Lipogenesis / Q000276:immunology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: C481673:Arg2 protein, mouse; D001119:Arginase
keywords: Arginase 2; Inflammation; Innate immunity; Liver fibrosis; Macrophage activation; Non-alcoholic fatty liver disease; Steatohepatitis