The Presence of p47phox in Liver Parenchymal Cells is a Key Mediator in the Pathogenesis of Alcoholic Liver Steatosis
Department of Medicince, Division of Gastroenterology
Fatty Liver, Alcoholic; NADPH Oxidase
Digestive System Diseases | Gastroenterology | Hepatology
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 kappaB (NF-kappaB), 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-kappaB 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-kappaB 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.
DOI of Published Version
Alcohol Clin Exp Res. 2012 Aug;36(8):1397-406. doi: 10.1111/j.1530-0277.2012.01739.x. Epub 2012 Feb 29. Link to article on publisher's site
Alcoholism, clinical and experimental research
Levin I, Petrasek J, Szabo G. (2012). The Presence of p47phox in Liver Parenchymal Cells is a Key Mediator in the Pathogenesis of Alcoholic Liver Steatosis. Gastroenterology Publications and Presentations. https://doi.org/10.1111/j.1530-0277.2012.01739.x. Retrieved from https://escholarship.umassmed.edu/gastroenterology_pp/105