Specific role for acyl CoA:Diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids.
Nonalcoholic fatty liver disease, characterized by the accumulation of triacylglycerols (TGs) and other lipids in the liver, often accompanies obesity and is a risk factor for nonalcoholic steatohepatitis and fibrosis. To treat or prevent fatty liver, a thorough understanding of hepatic fatty acid and TG metabolism is crucial. To investigate the role of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), a key enzyme of TG synthesis, in fatty liver development, we studied mice with global and liver-specific knockout of Dgat1. DGAT1 was required for hepatic steatosis induced by a high-fat diet and prolonged fasting, which are both characterized by delivery of exogenous fatty acids to the liver. Studies in primary hepatocytes showed that DGAT1 deficiency protected against hepatic steatosis by reducing synthesis and increasing the oxidation of fatty acids. In contrast, lipodystrophy (aP2-SREBP-1c436) and liver X receptor activation (T0901317), which increase de novo fatty acid synthesis in liver, caused steatosis independently of DGAT1. Pharmacologic inhibition of Dgat1 with antisense oligonucleotides protected against fatty liver induced by a high-fat diet.


CONCLUSIONS
Our findings identify a specific role for hepatic DGAT1 in esterification of exogenous fatty acids and indicate that DGAT1 contributes to hepatic steatosis induced by this mechanism.
Villanueva
Claudio J
CJ
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158, USA.
Monetti
Mara
M
Shih
Michelle
M
Zhou
Ping
P
Watkins
Steve M
SM
Bhanot
Sanjay
S
Farese
Robert V
RV
D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000172:deficiency*; D004041:Dietary Fats / Q000009:adverse effects; D005215:Fasting / Q000009:adverse effects; D005227:Fatty Acids / Q000008:administration & dosage / Q000009:adverse effects* / Q000096:biosynthesis; D005234:Fatty Liver / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016376:Oligonucleotides, Antisense / Q000494:pharmacology
D004041:Dietary Fats; D005227:Fatty Acids; D016376:Oligonucleotides, Antisense; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase