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

作者：Warner, Dennis R.; Liu, Huilin; Miller, Matthew E.; Ramsden, Christopher E.; Gao, Bin; Feldstein, Ariel. E.; Schuster, Susanne; McClain, Craig J.; Kirpich, Irina A.^*

来源：American Journal Of Pathology, 2017, 187(10): 2232-2245.

DOI：10.1016/j.ajpath.2017.06.008

• MEDIUM-CHAIN TRIGLYCERIDES
• FATTY LIVER
• NONALCOHOLIC STEATOHEPATITIS
• NEUTROPHIL INFILTRATION
• MOUSE MODEL
• 9-HYDROXYOCTADECADIENOIC ACID
• HYDROXYOCTADECADIENOIC ACIDS
• MACROPHAGE ACTIVATION
• INTESTINAL BARRIER
• LEUKOTRIENE B-4

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.

• 单位
  吉林大学