Alcohol abuse exacts a major toll on health and health costs in Veterans. Indeed, even though there is an epidemic of hepatitis C in the U.S., alcohol-related liver injury remains a higher cause of mortality. Studies from the Veterans Administration showed that patients with cirrhosis and superimposed alcoholic hepatitis had > 60% mortality over a four-year period of time, with most of those deaths occurring in the first few months. Thus, the prognosis for this stage of ALD is worse than many common types of cancer, such as breast, prostate and colon. Unfortunately, there is no FDA-approved therapy for any stage of ALD, and this makes the need for this proposed research even more compelling. 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, in an animal model of ALD. These findings led us to postulate that specific oxidized LA metabolites (OXLAMs) 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. We propose that OXLAMs contribute to the EtOH-induced hepatic inflammation and injury via two major mechanisms: 1) OXLAMs-mediated mitochondrial dysfunction, endoplasmic reticulum stress (ER stress) and hepatocyte death; and 2) OXLAM/TRPV1/Ca2+-mediated inflammasome activation and IL-1? release. The proposed studies will help elucidate the molecular mechanisms of alcohol-induced liver injury, including 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 heavy drinkers develop clinically important ALD. Our research will be achieved through 3 specific aims:
Aim 1. Evaluate whether OXLAMs exacerbate EtOH-mediated liver injury via induction of mitochondrial dysfunction, ER stress, and hepatocyte cell death in an animal model of ALD;
Aim 2. Determine whether OXLAMs contribute to an EtOH-induced hepatic pro-inflammatory response via OXLAM-TRPV1-mediated inflammasome activation and subsequent increase in IL-? release in an animal model of ALD.
Aim 3. Explore the role of OXLAMs in monocytes/macrophages inflammasome activation in Alcoholic Hepatitis in Veterans.
Alcohol abuse exacts a major toll on health and health costs in Veterans. Even though there is an 'epidemic' of hepatitis C in the U.S. and the Veterans Administration, alcohol-related liver injury remains a higher cause of mortality. Studies from the Veterans Administration showed that patients with cirrhosis and superimposed alcoholic hepatitis had > 60% mortality over a four-year period of time, with most of those deaths occurring in the first few months. Thus, the prognosis for this stage of ALD is worse than many common types of cancer, such as breast, prostate and colon. Unfortunately, there is no FDA-approved therapy for any stage of ALD, and this makes the need for this proposed research even more compelling. The proposed studies will help to better understand the molecular mechanisms of alcohol-induced liver and intestinal injury, including 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 heavy drinkers develop clinically important ALD.
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