Effects of Endogenous ω6:ω3 PUFA Ratio Reduction on Ileum Homeostasis and Liver Injury in Mice Chronically Fed Ethanol

Abstract

The objective of the current study was to test the hypothesis that increasing endogenous levels of w3 PUFAs alters gene expression profiles in the intestine of mice chronically fed an ethanol (EtOH) diet, leading to improved gut barrier and liver function, in a mouse model of alcoholic liver disease (ALD). ALD is a significant human health issue leading to increased morbibity and mortality resulting from liver dysfunction. Chronic alcohol consumption causes changes in intestinal permeability resulting in translocation of the gut luminal contents into the circulation. Therefore, a complete understanding of the mechanism(s) by which alcohol consumption alters gut barrier function is essential in order to develop therapeutic strategies to combat these effects. To test the above hypothesis, wild‐type and fat‐1 transgenic mice (which express an w6 fatty acid desaturase and therefore can directly convert w6 to w3 PUFAs) were fed a liquid diet with or without EtOH (pair‐fed, PF) for 6 weeks. Prior to euthanasia, a subset of the mice were challenged with LPS, which induces endotoxemia and is a frequent comorbidity to ALD. At the end of the study, liver and intestine pathology was evaluated and an RNA‐seq analysis was performed on ileum tissue. We identified numerous, statistically significant changes in ileum gene expression in fat‐1 mice when compared to wild‐type controls. Significant changes in the expression of genes that encode enzymes important for the metabolism and detoxification of EtOH were found in both pair‐fed and EtOH‐fed, LPS‐challenged mice. For example, the expression of Adh1 and Adh6a, two members of the alcohol dehydrogenase family, were significantly increased in the ileums of fat‐1 mice. In addition, several isoforms of aldehyde dehydrogenase were increased in fat‐1 mice, including Aldh1a7 and Aldh3b1, in both pair‐fed and EtOH/LPS‐treated animals. The expression of catalase, which metabolizes hydrogen peroxide, was increased and the expression of Cyp2e1 was decreased in PF fat‐1 mice, suggesting that these mice are better positioned to resist tissue damage as a result of reactive oxygen species. In mice fed only EtOH and not challenged with LPS, there was a significant change in the expression of genes important for xenobiotic metabolism. These include several cytochrome p450s (Cyp2c65, Cyp2d10, and Cyp2d34). Lastly, we found that the expression many genes involved in the metabolism of purines was significantly altered in the ileums of fat‐1 mice. For example, Entpd8 (ectonucleoside triphosphate diphosphohydrolase 8), Enpp3 (ectonucleotide pyrophosphatase/phosphodiesterase 3) and Ada (adenosine deaminase) were all increased in fat‐1 mice. The metabolism of adenosine is critically important for regulating immune function and therefore, altered purine metabolism may be one mechanism by which fat‐1 mice are protected from the toxic effects of chronic EtOH consumption. In summary, these data suggest that fat‐1 mice are much more efficient at metabolizing EtOH and the toxic metabolite, acetaldehyde, and have changes in purine metabolism that potentially have a beneficial effect on overall intestine function.Support or Funding InformationNational Institutes of HealthThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.