Lipidomic analysis of liver was performed by ESI-MS/MS. Results:

Ethanol caused a dose-dependent inhibitory effect on mRNA and protein expression of apoAV in WT hepatocytes. This induced the accumulation of excess triglyceride and the formation of numerous lipid droplets in apoAV KO, but not Tg hepatocytes vs. WT controls. After ethanol feeding, apoAV KO mice displayed rapid development of liver steatosis, subsequently evolving Protease Inhibitor Library from simple steatosis to ASH and then to liver fibrosis. WT mice developed only liver steatosis. Ethanol increased hepatic lysoPC levels, a known lipotoxic fatty acid metabolite, by enhancing its synthesis in KO mice compared to WT mice. Increased lysoPC induced hepatic lipoapoptosis through TNF by stimulating both caspase-induced apoptosis and reactive oxygen species (ROS)-mediated mitochondrial dysfunction in KO, but not WT mice. These alterations triggered ASH with a key histological feature of hepatocellular ballooning, and increased collagen secretion by hepatic stellate cells through activating profibro-genic genes and heat shock protein 47, leading

to liver fibrosis in KO mice. Conclusions: The apoAV KO mouse model closely recapitulates many characteristics of the pathogenic processes and histological patterns of ALD in patients. LysoPC may be a key trigger for ASH, similar to its proposed role in NASH. These innovative studies elucidate a critical role of apoAV in the pathogenesis of ALD. Disclosures: Brent A. Neuschwander-Tetri – Advisory Committees or Review Panels: Boehring-er-Ingelheim The following people have nothing http://www.selleckchem.com/PARP.html to disclose: David Q. Wang, Ornella de Bari, Bin Gao, Helen H. Wang, Piero Portincasa, Linda S. Zhang, David A. Ford, Patrick Tso Objective: In the liver, chronic alcohol consumption produces oxidative stress resulting in increased lipid peroxidation of membrane lipids to form highly reactive electrophilic a/p unsaturated aldehydes foremost of which is 4-hydroxynoneal

(4-HNE). In hepatocytes, a primary mechanism of reactive aldehyde disposal is by GSTA4-driven enzymatic conjugation with 上海皓元医药股份有限公司 GSH. We have recently reported that deletion of GSTA4-4 (GSTA4−/−) results in increased hepatocellular damage corresponding to an increase in lipid peroxidation following chronic Etoh consumption. Given that GSTA4 translocation reportedly occurs to the mitochondria, we hypothesized that increased hepatocellular damage in pair-fed (PF), ethanol (EtOH)-fed GSTA4−/− mice is due to increased mitochondrial carbonylation. Methods: Hepatic mitochondrial fractions were obtained from EtOH-fed or isocaloric PF (40 days) SV 129/J or GSTA4−/− mice. Overall carbonylation was assessed by immunohistochemistry, Western blotting and LC/MS/MS. Identified carbonylated proteins were further evaluated using bioinformatics analyses.