Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the world. It affects millions of patients worldwide each year. Although substantial progress has been made in ALD pathogenesis, the specific mechanisms 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 rich in linoleic acid (LA) exacerbated alcohol- mediated intestinal permeability and liver injury as compared with dietary saturated fat in an experimental animal model of ALD. In addition, our preliminary data show elevated levels of circulating oxidized LA metabolites (OXLAMs), specifically 9- and 13-hydroxy-octadecadienoic acids (9- and 13-HODEs), concomitant with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO), the key enzyme involved in the oxidation of LA. These findings provide initial evidence that OXLAMs, which are natural ligands to the transient receptor potential vanilloid 1 (TRPV1, subfamily V member 1), contribute to the pathogenesis of ALD. TRPV1 is a ligand-gated non-selective cation channel with high permeability for Ca2+. A number of recent studies have shown a critical role for intracellular Ca2+ in inflammasome activation. NLRP3 Inflammasome activation with release of highly pro-inflammatory cytokines interleukin-1? (IL-1?) and interleukin-18 (IL-18) is an important pro-inflammatory response in ALD. However, the molecular mechanisms contributing to the inflammasome priming and activation in ALD are not fully identified. Our central hypothesis is that dietary unsaturated fat (linoleic acid enriched) exacerbates alcohol-mediated liver inflammation and injury via oxidized linoleic acid metabolites that facilitate hepatic inflammasome activation. We propose that the OXLAM/TRPV1/Ca2+ signaling pathway is an upstream mechanism of inflammasome activation. To address our hypothesis, we propose the following specific aims.
Aim 1. Determine the role of oxidized linoleic acid metabolites (OXLAMs) and the 12/15-LO-mediated pathway of linoleic acid oxidation in the development and/or progression of ALD.
Aim 2. Assess whether hepatic inflammasome activation is mediated by an OXLAM-TRPV1-Ca2+ pathway in an animal model of ALD.
Aim 3. Determine the potential role of 12/15-LO, TRPV1 and OXLAMs in inflammasome activation in human Alcoholic Hepatitis. The proposal will provide a better understanding of alcohol-diet interactions and molecular mechanisms contributing to the pathogenesis of alcohol-induced liver inflammation and injury. The study will lead to identification of new therapeutic targets and potential dietary interventions for treating ALD, and provide a dietary mechanism to explain why only some heavy drinkers develop clinically important ALD. A combination of in vitro, in-vivo animal (gain and loss of function) and human studies will be employed.
My RO1 application investigates the role of dietary fat in the development of alcoholic liver disease. Specifically, the project directly examines how dietary linoleic fatty acid and its oxidized products promote alcohol-mediated liver injury.
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