title: The presence of p47phox in liver parenchymal cells is a key mediator in the pathogenesis of alcoholic liver steatosis.
abstract: BACKGROUND
  Reactive oxygen species contribute to steatosis and inflammation in alcoholic liver disease (ALD). Here, we evaluated the selective contribution of p47phox, a critical subunit of nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase complex, in liver parenchymal cells and in bone marrow (BM)-derived cells.
  
  
  METHODS
  Female C57Bl/6 wild type [WT], total body p47phox-deficient knockout [KO] or p47phox chimera mice generated by BM transplantation of p47phox-KO-BM into irradiated WT mice (WT/p47phox-KO-BM mice) received 5% Lieber-DeCarli alcohol or control (pair feeding) diet for 4 weeks.
  
  
  RESULTS
  Alcohol-induced liver steatosis as measured by Oil Red O staining and serum triglyceride up-regulation were prevented in p47phox-KO mice but not in WT/p47phox-KO-BM chimeras compared to WT controls. Serum alanine aminotransferase (ALT) was significantly increased in alcohol-fed WT mice but not in p47phox-KO mice compared to pair-fed controls. There was no protection from alcohol-induced increase in ALT and liver damage in the WT/p47phox-KO-BM mice. Alcohol-induced liver steatosis was accompanied by up-regulation of the lipid droplet-stabilizing protein, adipocyte differentiation-related protein (ADRP), and the fatty acid synthesis-associated genes, fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACACA). Total body deficiency in p47phox but not selective absence of p47phox in BM-derived cells prevented alcohol-induced up-regulation of ADRP, FASN, and ACACA in the liver. Finally, alcohol-induced activation and DNA binding of nuclear factor κB (NF-κB), a master regulator of inflammation, were significantly increased after alcohol feeding in WT but not in p47phox-KO mice. Selective deficiency of p47phox in BM-derived cells (WT/p47phox-KO-BM chimera) failed to prevent NF-κB induction after alcohol feeding.
  
  
  CONCLUSIONS
  Total body deficiency in p47phox subunit of NADPH oxidase complex protects mice from alcohol-induced liver steatosis via mechanisms involving ADRP, FASN, and ACACA as well as from alcohol-induced NF-κB activation. In contrast, selective absence of p47phox in BM-derived cells fails to provide protection via these mechanisms. These results suggest that p47phox in parenchymal cells plays a critical role in the pathogenesis of ALD.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, 01605, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Levin
authors.forename: Jan
authors.initials: J
authors.lastname: Petrasek
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D000431:Ethanol / Q000633:toxicity; D005235:Fatty Liver, Alcoholic / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D014280:Triglycerides; D000431:Ethanol; D012313:RNA; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D001219:Aspartate Aminotransferases