Effect of Elevated ω‐3/ω‐6 PUFA ratio on High‐Fat Diet and Acute Ethanol‐induced Obesity, Glucose Intolerance and Liver Injury in Mice

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Rationale and ObjectivesNonalcoholic and alcoholic fatty liver disease (ALD and NAFLD) are both serious health and socioeconomic problems worldwide, with similar pathological spectra, ranging from simple hepatic steatosis to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. ALD and NAFLD have also several similar risk factors, including certain dietary factors and obesity. Human and animal studies have demonstrated that a Western diet, rich in ω‐6 polyunsaturated fatty acids (PUFAs) and low in ω‐3 PUFAs, exacerbates NAFLD and ALD. In addition, obese alcohol drinkers might be at an increased risk of developing more severe liver injury. The objective of the present study was to investigate whether a decrease in ω6 PUFAs with subsequent increase in the ω‐3/ω‐6 PUFA ratio ameliorates metabolic derangements and liver injury in a two‐hit model of long‐term HFD feeding plus a single EtOH binge administration.MethodsFemale fat‐1+/− (mice with the ability to endogenously convert ω6 to ω3 PUFA) and WT littermates were fed low or high fat diets (LFD and HFD, 10% and 60%, respectively) for 12 weeks. On the last day of the experiment, mice received a single dose of EtOH (5 g/kg) by oral gavage. Animals were euthanized 9h‐post gavage. Metabolic parameters and liver injury were evaluated.ResultsLong‐term HFD feeding resulted in alterations of metabolic parameters in both genotypes. However, compared to WT, fat‐1+/− gained significantly less body weight (BW), and had less parametrial fat at the end of the study. This could be due to significantly lower food consumption in fat‐1+/− mice. Liver weight/BW ratio was equally reduced in HFD‐fed mice compared to LFD. While the type of the diet did not affect the pancreas weight/BW ratio, ethanol administration resulted in an opposite effect on this parameter in WT (increase) and fat1−/+ mice (decrease). Analysis of liver injury revealed that HFD led to similar induction of ALT levels (a marker of liver injury) in both genotypes, which was further equally elevated by ethanol administration. However, ethanol challenge resulted in significant increase in ALT levels in LFD fed mice in WT but not fat1−/+ littermates.ConclusionsIncrease in endogenous ω‐3/ω‐6 PUFA ratio was not beneficial against HFD and binge EtOH‐induced liver damage (two‐hit model), however, mice fed a LFD were protected against EtOH‐mediated liver injury. The molecular mechanisms underlying these effects needs to be further investigated.Support or Funding InformationSupported by grants from NIH and Veterans AdministrationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.