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Am J Pathol. 2017 Oct;187(10):2232-2245. doi: 10.1016/j.ajpath.2017.06.008.

Dietary Linoleic Acid and Its Oxidized Metabolites Exacerbate Liver Injury Caused by Ethanol via Induction of Hepatic Proinflammatory Response in Mice.

Author information

1
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.
2
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; College of Life Science, Jilin University, Changchun, China.
3
National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland; National Institute on Aging, Baltimore, Maryland.
4
National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.
5
Division of Gastroenterology, Department of Pediatrics, University of California San Diego, San Diego, California.
6
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky; Robley Rex Veterans Medical Center, Louisville, Kentucky; Hepatobiology and Toxicology Program, University of Louisville School of Medicine, Louisville, Kentucky; University of Louisville Alcohol Research Center, University of Louisville School of Medicine, Louisville, Kentucky.
7
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky; Hepatobiology and Toxicology Program, University of Louisville School of Medicine, Louisville, Kentucky; University of Louisville Alcohol Research Center, University of Louisville School of Medicine, Louisville, Kentucky. Electronic address: i0kirp01@louisville.edu.

Abstract

Alcoholic liver disease is a major human health problem leading to significant morbidity and mortality in the United States and worldwide. Dietary fat plays an important role in alcoholic liver disease pathogenesis. Herein, we tested the hypothesis that a combination of ethanol and a diet rich in linoleic acid (LA) leads to the increased production of oxidized LA metabolites (OXLAMs), specifically 9- and 13-hydroxyoctadecadienoic acids (HODEs), which contribute to a hepatic proinflammatory response exacerbating liver injury. Mice were fed unsaturated (with a high LA content) or saturated fat diets (USF and SF, respectively) with or without ethanol for 10 days, followed by a single binge of ethanol. Compared to SF+ethanol, mice fed USF+ethanol had elevated plasma alanine transaminase levels, enhanced hepatic steatosis, oxidative stress, and inflammation. Plasma and liver levels of 9- and 13-HODEs were increased in response to USF+ethanol feeding. We demonstrated that primarily 9-HODE, but not 13-HODE, induced the expression of several proinflammatory cytokines in vitro in RAW264.7 macrophages. Finally, deficiency of arachidonate 15-lipoxygenase, a major enzyme involved in LA oxidation and OXLAM production, attenuated liver injury and inflammation caused by USF+ethanol feeding but had no effect on hepatic steatosis. This study demonstrates that OXLAM-mediated induction of a proinflammatory response in macrophages is one of the potential mechanisms underlying the progression from alcohol-induced steatosis to alcoholic steatohepatitis.

PMID:
28923202
PMCID:
PMC5808136
DOI:
10.1016/j.ajpath.2017.06.008
[Indexed for MEDLINE]
Free PMC Article

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