This is a resubmission of an Extramural/Intramural Alcohol Research Collaboration (U01) Application entitled Oxidized Metabolites of Linoleic Acid in Alcohol-induced Liver Injury. 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 a core abnormality responsible for liver injury in ALD. Based on our extensive preliminary findings we propose the CENTRAL HYPOTHESIS that oxidized linoleic acid (LA) metabolites (OXLAMs) generated via the 12/15-LO mediated pathway play a critical role in the development and progression of alcohol-mediated hepatic and intestinal injury. We have established a collaborative team with extensive expertise and unique resources that will allow us to accomplish our goals by using in vivo experimental animal models of ALD, in vitro cell culture models, and collaborating with the unique human populations of an ongoing NIAAA Clinical Center randomized trial on dietary linoleic acid (LA) reduction and an NIAAA sponsored U01 clinical trial on alcoholic hepatitis (AH). State-of-the-art technologies including Lipidomics (LC/ESI/MS/MS), Seahorse (to investigate mitochondria dysfunction), Cellomics (the high-throughput technique for cell image-acquisition and analysis) will be utilized in this proposal. FIRST, we will test the hypothesis that OXLAMs are specific mediators of liver damage and intestinal barrier disruption in ALD. We will establish the role of dietary LA and OXLAMs in the induction of hepatic steatosis/injury and intestinal hyper-permeability in murine models of ALD. SECOND, we will evaluate in in vitro systems potential mechanisms by which OXLAMs enhance ethanol-mediated liver damage and disruption of intestinal barrier integrity. We will determine the effect of OXLAMs and their interactions with alcohol on mitochondrial function in hepatocytes and integrity of tight junctions in intestinal epithelium. THIRD, we will evaluate the ability of controlled dietary lowering of LA in humans to reduce circulating OXLAMs, endotoxin/gut permeability, and liver steatosis/injury (NIAAA intramural RCT). We will test the hypothesis that, compared to a control diet containing 8 % of energy as LA, lowering LA to 1% of energy for 12 weeks will result in significant reductions in: liver steatosis assessed by 3T-MRI; OXLAM and LA content of plasma, circulating endotoxin, and serum CK-18 (total and fragmented) levels (two robust markers of hepatocyte injury). FINALLY, we will establish levels of OXLAMs in human Alcoholic Hepatitis and their relation to disease severity and mortality (NIAAA U01 program). This study will help to elucidate a novel biochemical pathway involved in the pathogenesis of ALD. The findings could provide novel targets for biomarkers and drug development, and could identify a potential nutritional strategy for ameliorating liver disease.

Public Health Relevance

Alcoholic liver disease remains a major cause of chronic illness and mortality. The specific mechanisms responsible for development and progression are incompletely understood. Our studies will serve as powerful tools to identify novel therapeutic interventions for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA022489-03
Application #
9093663
Study Section
Neuroscience Review Subcommittee (AA)
Program Officer
Wang, Joe
Project Start
2014-09-01
Project End
2019-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Eguchi, Akiko; Feldstein, Ariel E (2018) Extracellular vesicles in non-alcoholic and alcoholic fatty liver diseases. Liver Res 2:30-34
Ramsden, Christopher E; Hennebelle, Marie; Schuster, Susanne et al. (2018) Effects of diets enriched in linoleic acid and its peroxidation products on brain fatty acids, oxylipins, and aldehydes in mice. Biochim Biophys Acta Mol Cell Biol Lipids 1863:1206-1213
Wree, Alexander; Inzaugarat, Maria Eugenia; Feldstein, Ariel E (2018) Transmembrane BAX Inhibitor motif-containing 1, a novel anti-inflammatory approach for nonalcoholic steatohepatitis treatment. Hepatology 67:438-441
Kharbanda, Kusum K; Ronis, Martin J J; Shearn, Colin T et al. (2018) Role of Nutrition in Alcoholic Liver Disease: Summary of the Symposium at the ESBRA 2017 Congress. Biomolecules 8:
Ghosh Dastidar, Shubha; Warner, Jeffrey B; Warner, Dennis R et al. (2018) Rodent Models of Alcoholic Liver Disease: Role of Binge Ethanol Administration. Biomolecules 8:
Schuster, Susanne; Johnson, Casey D; Hennebelle, Marie et al. (2018) Oxidized linoleic acid metabolites induce liver mitochondrial dysfunction, apoptosis, and NLRP3 activation in mice. J Lipid Res 59:1597-1609
He, Liqing; Prodhan, Md Aminul Islam; Yuan, Fang et al. (2018) Simultaneous quantification of straight-chain and branched-chain short chain fatty acids by gas chromatography mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 1092:359-367
Vatsalya, Vatsalya; Kong, Maiying; Cave, Matthew C et al. (2018) Association of serum zinc with markers of liver injury in very heavy drinking alcohol-dependent patients. J Nutr Biochem 59:49-55
Prodhan, Md Aminul Islam; Yin, Xinmin; Kim, Seongho et al. (2018) Surface fitting for calculating the second dimension retention index in comprehensive two-dimensional gas chromatography mass spectrometry. J Chromatogr A 1539:62-70
Warner, Dennis R; Liu, Huilin; Miller, Matthew E et al. (2017) Dietary Linoleic Acid and Its Oxidized Metabolites Exacerbate Liver Injury Caused by Ethanol via Induction of Hepatic Proinflammatory Response in Mice. Am J Pathol 187:2232-2245

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