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The Presence of p47phox in Liver Parenchymal Cells is a Key Mediator in the Pathogenesis of Alcoholic Liver Steatosis
Author(s) -
Levin Ivan,
Petrasek Jan,
Szabo Gyongyi
Publication year - 2012
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2012.01739.x
Subject(s) - steatosis , endocrinology , medicine , fatty liver , alcoholic liver disease , nicotinamide adenine dinucleotide phosphate , biology , fatty acid synthase , lipid droplet , chemistry , oxidase test , biochemistry , lipid metabolism , cirrhosis , enzyme , disease
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% L ieber– D e C arli alcohol or control (pair feeding) diet for 4 weeks. Results Alcohol‐induced liver steatosis as measured by O il R ed 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‐ C o A 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 ‐κ B ), 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 ‐κ B 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 ‐κ B 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.