Disclosures: The following people have nothing to

disclose: Huquan Yin, Xiaomei Liang, Joanne M. Ajmo, Brian Finck, Min You BACKGROUND: Alcohol (Al) and weight gain (WG) independently contribute to significant liver disease burden. Concurrent presence of Al and WG can substantially impact liver disease phenotype conceivably by biologically active lipid metabolites. AIMS: To characterize the hepatic lipidome in a mouse model of regular (RAl) and binge (B) alcohol consumption that gains weight GPCR Compound Library high throughput on western diet (WD) and potential interactions of WG, RAl and binge drinking on disease phenotype. METHODS: Male C57Bl/6 mice received 8 wk chow and WD with and without Al. Another group of WD+RAl fed mice received a weekly alcohol binge while keeping constant the total Al consumed. Molecular lipid species including eicosanoids, ceramides, and sphingolipids were identified by LC/MS lipidomic techniques. Inter-group comparisons were performed using AN〇VA followed by Tukey’s post-hoc tests with adjustment for multiple testing as appropriate. RESULTS: Five groups (Chow, Chow+RAl, WD, WD+RAl and WD+RAl+B) were studied. Mice gained weight on WD (+21. 5%), WD+RAl (+7. 8%) and WD+RAl+B (+10.3%). RAl resulted in mononuclear cell inflammation, perisinusoidal and pericellular fibrosis

while weekly binge induced intense neutrophilic infiltration and 2-fold increase in AST/ALT ratio in WD+RAl+B mice simulating severe alcoholic hepatitis in humans. Lipidomic selleck inhibitor changes: 141/268 (52%) measured lipids were significantly changed in one or more intergroup comparison. Pro-inflammatory lipoxygenase (L〇X) metabolites, 5- and 8-hydroxyeicosatetraenoic (HETE) acids and lipid peroxidation products 9- and 13- hydroxy-octadecadienoic (H〇DE) acid were increased. Interaction effect of RAl:

RAl in WD fed mice with WG dramatically increased hepatic cholesteryl ester (CE) content while a striking increase in diacylglycerol (DAG) species was noted independent of WG. Both 5- and 8-HETE were Loperamide increased in mice fed WD with WG and RAl intake. Interaction effect of RAl+B: Interestingly, RAl or WD alone had only minor effects on hepatic eicosanoids. However, concurrent RAl+B in WD fed mice with WG revealed a consistent trend of increased non-enzymatic eicosanoids (9- & 13-H〇DEs) and a striking significant increase in prostaglandin E2 with RAl (+150%) and RAl+B (+650%). In addition, ceramides were significantly decreased in the RAl+B group and downstream lactoylceramides and other related metabolites showed a consistent increasing trend. CONCLUSION: Concurrent regular alcohol with binge exposure and weight gain on western diet leads to profound pro-inflammatory and oxidative injury compared to weight gain alone. This is mediated via ceramides and related pathways and by eicosanoid metabolites of nonenzymatic and LOX pathways. Disclosures: Puneet Puri – Advisory Committees or Review Panels: Health Diagnostic Laboratory Inc.; Consulting: NPS Pharmaceuticals Inc.