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)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AA022489-01A1
Application #
8705229
Study Section
Biomedical Research Review Subcommittee (AA)
Program Officer
Brooks, Pj
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Inzaugarat, Maria Eugenia; Wree, Alexander; Feldstein, Ariel E (2016) Hepatocyte mitochondrial DNA released in microparticles and toll-like receptor 9 activation: A link between lipotoxicity and inflammation during nonalcoholic steatohepatitis. Hepatology 64:669-71
Alkhouri, Naim; Feldstein, Ariel E (2016) Noninvasive diagnosis of nonalcoholic fatty liver disease: Are we there yet? Metabolism 65:1087-95
Kirpich, Irina A; Petrosino, Joseph; Ajami, Nadim et al. (2016) Saturated and Unsaturated Dietary Fats Differentially Modulate Ethanol-Induced Changes in Gut Microbiome and Metabolome in a Mouse Model of Alcoholic Liver Disease. Am J Pathol 186:765-76
Povero, Davide; Feldstein, Ariel E (2016) Novel Molecular Mechanisms in the Development of Non-Alcoholic Steatohepatitis. Diabetes Metab J 40:1-11
Ghare, Smita S; Donde, Hridgandh; Chen, Wei-Yang et al. (2016) Acrolein enhances epigenetic modifications, FasL expression and hepatocyte toxicity induced by anti-HIV drug Zidovudine. Toxicol In Vitro 35:66-76
Wree, Alexander; Mehal, Wajahat Z; Feldstein, Ariel E (2016) Targeting Cell Death and Sterile Inflammation Loop for the Treatment of Nonalcoholic Steatohepatitis. Semin Liver Dis 36:27-36
Arrese, Marco; Cabrera, Daniel; Kalergis, Alexis M et al. (2016) Innate Immunity and Inflammation in NAFLD/NASH. Dig Dis Sci 61:1294-303
Eguchi, Akiko; De Mollerat Du Jeu, Xavier; Johnson, Casey D et al. (2016) Liver Bid suppression for treatment of fibrosis associated with non-alcoholic steatohepatitis. J Hepatol 64:699-707
Eguchi, Akiko; Lazic, Milos; Armando, Aaron M et al. (2016) Circulating adipocyte-derived extracellular vesicles are novel markers of metabolic stress. J Mol Med (Berl) 94:1241-1253
Kirpich, Irina A; Miller, Matthew E; Cave, Matthew C et al. (2016) Alcoholic Liver Disease: Update on the Role of Dietary Fat. Biomolecules 6:1

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