Dietary Macronutrient Composition Determines the Contribution of DGAT1 to Alcoholic Steatosis

BACKGROUND: The first stage of alcoholic liver disease is hepatic steatosis. While alcohol is known to profoundly impact hepatic lipid metabolism, gaps in our knowledge remain regarding the mechanisms leading to alcohol‐induced hepatic triglyceride (TG) accumulation. As the sole enzymes catalyzing the final step in TG synthesis, diacylglycerol O‐acyltransferase (DGAT) 1 and 2 are potentially important contributors to alcoholic steatosis. Our goal was to study the effects of dietary fat content on alcohol‐induced hepatic TG accumulation, and the relative contribution of DGAT1 and DGAT2 to alcoholic steatosis. METHODS: These studies were carried out in wild‐type (WT) mice fed alcohol‐containing high‐fat or low‐fat formulations of Lieber‐DeCarli liquid diets, as well as follow‐up studies in Dgat1 (−/−) mice. RESULTS: A direct comparison of the low‐fat and high‐fat liquid diet in WT mice revealed surprisingly similar levels of alcoholic steatosis, although there were underlying differences in the pattern of hepatic lipid accumulation and expression of genes involved in hepatic lipid metabolism. Follow‐up studies in Dgat1 (−/−) mice revealed that these animals are protected from alcoholic steatosis when consumed as part of a high‐fat diet, but not a low‐fat diet. CONCLUSIONS: Dietary macronutrient composition influences the relative contribution of DGAT1 and DGAT2 to alcoholic steatosis, such that in the context of alcohol and a high‐fat diet, DGAT1 predominates.