Role of Dietary Fat in Alcoholic Liver Disease

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Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the US and worldwide. Although substantial progress has been made in ALD pathogenesis, the specific mechanism(s) responsible for ALD development and progression remain incompletely understood. Importantly, there is no FDA approved therapy for any stage of ALD. Recent studies from our laboratory and others demonstrated that dietary unsaturated fat rich in linoleic acid (LA) increased intestinal permeability to gut-derived endotoxins and exacerbated liver inflammation and injury 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), and concomitant up-regulation of hepatic 12/15 lipoxygenase (12/15-LO), the key enzyme involved in the oxidation of LA. These findings suggest that OXLAMs, which act as 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 interleukin-1β (IL-1β) and interleukin-18 (IL-18) is an important pro- inflammatory response in ALD. Many factors are involved in inflammasome priming and activation network, including gut-derived endotoxin lipopolysaccharide (LPS). These findings in conjunction with our preliminary data have led us to hypothesize that dietary unsaturated fat (linoleic acid enriched) exacerbates alcohol- mediated liver inflammation and injury via oxidized linoleic acid metabolites that induce gut barrier disruption and hepatic inflammasome activation. To address our hypothesis, we propose the following four specific aims: Aim 1. Determine the role of dietary unsaturated fat, specifically linoleic acid and its oxidation products, in the development and/or progression of ALD. Aim 2. Assess whether hepatic inflammasome activation is mediated by OXLAMs-TRPV1-Ca2+ pathway in an animal model of ALD. Aim 3. Evaluate the molecular mechanism(s) by which dietary saturated fat attenuates and unsaturated fat exacerbates alcohol- mediated gut barrier disruption, endotoxemia and liver injury. Aim 4. Explore the role of OXLAMs, 12/15-LO and TRPV1 in monocyte inflammasome activation in human alcoholic hepatitis. The proposed studies will lead to a better understanding of the 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 drug 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. This proposal extensively interacts with other projects, pilots, and cores, and it incorporates the ULARC theme of nutrition and alcohol-induced organ injury.