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Characterization of hepatic w‐6 and w‐3 PUFA Oxilipins in Ethanol‐Induced Liver Injury in Mice
Author(s) -
Warner Dennis,
Dastidar Shubha Gosh,
Liu Huilin,
McClain Craig,
Kirpich Irina
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.813.1
Subject(s) - steatosis , steatohepatitis , liver injury , alcoholic liver disease , fatty liver , triglyceride , liver disease , cirrhosis , chemistry , polyunsaturated fatty acid , medicine , endocrinology , pharmacology , biochemistry , cholesterol , fatty acid , disease
/Aim Alcoholic liver disease (ALD) is a significant health problem with a high morbidity and mortality. ALD progresses through the course of several pathologies including steatosis, steatohepatitis, and cirrhosis. There are no effective FDA‐approved medications to prevent or treat any stage of ALD, and the molecular mechanisms underlying ALD development and progression are not completely understood. Identifying new mechanisms and novel therapeutic targets in ALD is of paramount importance. The goal of the present study was to examine the impact of ethanol (EtOH) and different types of dietary fat on the hepatic oxylipins, oxidized metabolites of ω‐3 and ω‐6 PUFAs, with the objective of identifying novel metabolic pathways and bioactive lipid compounds associated with EtOH‐induced liver damage, which might be potential novel biomarkers and/or therapeutic targets for the disease. Materials and Methods C57BL/6 male mice were fed EtOH‐containing diets for 10 days followed by a single EtOH gavage. Two different types of fat were utilized: corn oil (unsaturated fat, USF), and a combination of medium chain triglyceride oil and beef tallow (saturated fat, SF). Liver steatosis, inflammation, and injury were evaluated. HPLC/MS technology was used for lipidomic analysis in the liver samples. Results Mice fed USF+EtOH had significantly elevated plasma ALT levels (a marker of liver injury), hepatic fat accumulation, and up‐regulation of the pro‐inflammatory cytokine genes, Tnf‐α, Mcp1, Il‐1b and Hmgb1 (a marker of liver injury), compared to mice fed SF+EtOH. Among linoleic acid (LA, ω‐6) metabolites, 9‐ and 13‐HODEs, and 9,10‐DiHOME and 12,13‐DiHOME (which are generally considered as pro‐inflammatory mediators of LOX and CYP/sEH pathways, respectively) were significantly elevated in USF+EtOH vs SF+EtOH group. A significant increase was also observed in USF+EtOH vs SF+EtOH for arachidonic acid (AA, ω‐6) metabolites with known pro‐inflammatory, pro‐apoptotic and neutrophil chemotactic activities, including 5‐, 8‐, 9‐, 11‐, 15‐, and 20‐HETEs, and 8,9‐DIHETrE and 11,12‐DIHETrE . A strong positive correlation was observed between 8,9‐DIHETrE and Mcp1 , and 11,12‐DIHETrE and Hmgb1 . LXA4 (AA, LOX), which possesses some anti‐inflammatory properties, was elevated in USF+EtOH vs USF as well as SF+EtOH groups. Among ω3 fatty acids we observed the increase in metabolites of EPA (5‐ and 18‐HEPEs), and DHA, such as 4‐, 7‐, 10‐, 11‐, 13‐, 16‐, and 20‐HDoHE, and 10S,17S‐DiHDoHE (known as protectin DX) in USF+EtOH vs USF group. The observation that some metabolites with known pro‐ and antiinflammatory properties were simultaneously increased in the USF+EtOH group suggested that inflammation and resolution of inflammation in this model are tightly connected processes. Conclusion We identify a panel of bioactive lipid metabolites that were associated with EtOH‐mediated liver damage; these metabolites might be potential new biomarkers and therapeutic targets for the disease. Further studies examining the role of these mediators in ALD are warranted. Support or Funding Information Supported by grants from NIH and Veterans Administration This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .