Specific Role for Acyl CoA:Diacylglycerol Acyltransferase 1 (Dgat1) in Hepatic Steatosis Due to Exogenous Fatty Acids

Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in hepatocytes of people who consume little to no alcohol (1–3). Chronic lipid accumulation in the liver (hepatic steatosis) is a risk factor for nonalcoholic steatohepatitis, an inflammatory condition in some patients with fatty liver (4). NAFLD is the most common cause of abnormal liver enzyme tests (5), is associated with obesity and insulin resistance, and is increasing in prevalence, affecting ~30 million adults in the U.S., making it the most common liver disorder (2, 6). NAFLD portends epidemic problems for public health, and a better understanding of the pathways that regulate lipid accumulation in the liver is crucial for developing effective therapies for hepatic steatosis. Lipids that accumulate in hepatic steatosis are mainly triacylglycerols (TGs). After adipose tissue, the liver has perhaps the largest capacity to synthesize and store TGs (7). TGs are products of the glycerol phosphate synthesis pathway, in which fatty acyl moieties are joined to glycerol via ester bonds (8, 9). FAs in the liver may come from exogenous sources (e.g., dietary fat or mobilization from white adipose tissue (WAT) during fasting) or from endogenous de novo synthesis promoted by leptin deficiency or high levels of circulating insulin and glucose (1, 10–12). The final step in TG synthesis is catalyzed by DGAT enzymes. Mammals have two DGAT enzymes that are members of distinct gene families (13, 14). Both are expressed widely in tissues and in the livers of mice and humans (13, 15). Increased levels of DGAT1 mRNA, in particular, occur in human livers with NAFLD (16), underscoring the importance of defining the role of DGAT1 in this tissue. Mice lacking Dgat1 (Dgat1−/−) are viable, have reduced tissue TG levels, exhibit increased sensitivity to insulin and leptin, and are protected against diet-induced obesity through increased energy expenditure (17, 18). However, DGAT1’s function in hepatic steatosis has not been fully explored. To investigate the role of DGAT1 in hepatic steatosis, we studied mice with global (17) and liver-specific knockout of Dgat1 under conditions that promote hepatic steatosis. These included a high-fat diet, fasting (in which lipids are mobilized from the WAT to the liver), and two conditions in which endogenous FA synthesis is greatly increased—genetically induced lipodystrophy (19) and treatment with the liver X receptor (LXR) agonist T0901317 (20). Relevant to clinical therapies, we also determined whether knockdown of Dgat1 expression with antisense oligonucleotides (ASO) protects against diet-induced hepatic steatosis.