Oxidized Linoleic Acid metabolites (OXLAMs) play a critical role in the development and progression of alcohol-mediated hepatic injury

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Alcoholic liver disease (ALD) remains a major cause of chronic illness and death. Despite extensive investigation into ALD pathogenesis, the specific mechanisms responsible for development and progression are incompletely understood. Increased oxidative stress is thought to be a core abnormality responsible for liver injury in ALD. It is hypothesized that specific oxidation products of linoleic acid (LA), the most abundant polyunsaturated fatty acid in human diets, play a direct causal role in ALD. Oxidation products of LA, called OXLAMs, are formed enzymatically via the action of 12/15-lipoxygenase (12/15-LO). It has been shown that OXLAMs are elevated in the circulation of rodents fed an ethanol diet (Lieber-DeCarli diet) as well as in patients with steatohepatitis and that they lead to mitochondrial dysfunction and Nlrp3 inflammasome activation in WT mice. This project proposes the central hypothesis that OXLAMs generated via the 12/15-LO-mediated pathway play a critical role in the development and progression of alcohol-mediated hepatic injury. Therefore, gain and loss of function approaches will be used (12/15- LO knockout, 12/15- LO knockin, wild-type mice). In vitro studies on primary cells will be performed to determine the effects of OXLAMs and their interactions with alcohol on mitochondrial function and Nlrp3 inflammasome activation. This project will help to elucidate a novel biochemical pathway involved in the pathogenesis of ALD. If successful, the findings could provide novel targets for both biomarker and drug development, and could identify a potential nutritional strategy for ameliorating liver disease.