Differential requirements of triglyceride synthesis enzymes in the development of hepatic steatosis

Non-alcoholic fatty liver disease, a condition characterized by the accumulation of triacylglycerols in the liver, often accompanies obesity and can lead to steatohepatitis and cirrhosis. The synthesis of triacylglycerol is catalyzed by the acyl CoA:diacylglycerol acyltransferase (DGAT) enzymes, DGAT1 and DGAT2, and previous studies suggested different physiological roles for these enzymes. Here we investigated the role of DGAT1 in the development of hepatic steatosis. Whole animal and liver-specific deficiency of DGAT1 inhibited steatosis induced by a high-fat diet or fasting but not by conditions that increase de novo fatty acid synthesis in the liver, such as lipodystrophy or treatment with an LXR agonist. Instead, triglyceride synthesis coupled to fatty acid synthesis appears to be linked to DGAT2. Our studies identify mechanisms of hepatic steatosis that are dependent and independent of DGAT1 function in the liver and provide insights that may have implications for the treatment of fatty liver disease