Alcoholic liver disease (ALD) ranks among the major causes of morbidity and mortality in the world, and affects millions of patients worldwide each year. Despite the progress made on ALD pathogenesis, the specific mechanism(s) responsible for ALD development and progression remain poorly understood. Importantly, there is no FDA approved therapy for any stage of ALD. Recent studies from our laboratory and others have demonstrated that dietary unsaturated fat, specifically rich in linoleic acid (LA), exacerbated alcohol-mediated liver and intestinal injury in an experimental animal model of ALD. Our preliminary data show elevated levels of circulating oxidized LA metabolites, specifically 9- and 13-hydroxy-octadecadienoic acids (9-and 13-HODEs) in parallel with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO), a key enzyme involved in the oxidation of LA. These findings have led us to postulate that specific oxidized LA metabolites (OXLAMs) may play a significant role in ALD. OXLAMs are natural ligands to the transient receptor potential vanilloid 1 (TRPV1), a ligand-gated non-selective cation channel with high permeability for Ca2+. Recent studies demonstrate a critical role for Ca2+ release in inflammasome activation, which are key signaling platforms for stressor-induced pathogenesis, and which, upon activation, trigger the release of highly pro-inflammatory cytokines interleukin-1? (IL-1?) and interleukin-18 (IL-18). IL-1? release is thought to be a critical mediator of inflammation and thus, serves as a potential therapeutic target for treating hepatic inflammation in ALD. Based on our own and other published findings, our CENTRAL HYPOTHESIS is that OXLAMs play a significant role in the development and progression of ALD. We hypothesize that OXLAMs contribute to the EtOH- induced hepatic inflammation and injury via two mechanisms: 1) OXLAMs-mediated mitochondrial dysfunction and hepatocyte death; and 2) OXLAM/TRPV1/Ca2+-mediated inflammasome activation and IL-1? release. The proposed studies will lead to better understanding of molecular mechanisms contributing to the pathogenesis of alcohol-induced liver inflammation and injury. These studies will also help us to better understand alcohol-diet interactions, which may lead to identification of new therapeutic targets and potential dietary interventions for treating ALD, as well as help to explain why only some people who drink heavily develop clinically important ALD. A combination of in vitro, in-vivo animal (knockouts and chimeric mouse models) and human studies will be employed.
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