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.