Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice.
In this study, we investigated the role of acyl-coenzyme A:diacylglycerol acyltransferase 2 (DGAT2) in glucose and lipid metabolism in obese mice by reducing its expression in liver and fat with an optimized antisense oligonucleotide (ASO). High-fat diet-induced obese (DIO) C57BL/6J mice and ob/ob mice were treated with DGAT2 ASO, control ASO, or saline. DGAT2 ASO treatment reduced DGAT2 messenger RNA (mRNA) levels by more than 75% in both liver and fat but did not change DGAT1 mRNA levels in either of these tissues, which resulted in decreased DGAT activity in liver but not in fat. DGAT2 ASO treatment did not cause significant changes in body weight, adiposity, metabolic rate, insulin sensitivity, or skin microstructure. However, DGAT2 ASO treatment caused a marked reduction in hepatic triglyceride content and improved hepatic steatosis in both models, which was consistent with a dramatic decrease in triglyceride synthesis and an increase in fatty acid oxidation observed in primary mouse hepatocytes treated with DGAT2 ASO. In addition, the treatment lowered hepatic triglyceride secretion rate and plasma triglyceride levels, and improved plasma lipoprotein profile in DIO mice. The positive effects of the DGAT2 ASO were accompanied by a reduction in the mRNA levels of several hepatic lipogenic genes, including SCD1, FAS, ACC1, ACC2, ATP-citrate lyase, glycerol kinase, and HMG-CoA reductase. In conclusion, reduction of DGAT2 expression in obese animals can reduce hepatic lipogenesis and hepatic steatosis as well as attenuate hyperlipidemia, thereby leading to an improvement in metabolic syndrome.
Department of Antisense Drug Discovery, Isis Pharmaceuticals, Inc., 2292 Faraday Avenue, Carlsbad, CA 92008, USA.
Xing Xian
XX
Yu
Susan F
SF
Murray
Sanjay K
SK
Pandey
Sheri L
SL
Booten
Dingjiu
D
Bao
Xiu-Zhen
XZ
Song
Susan
S
Kelly
Songyuan
S
Chen
Robert
R
McKay
Brett P
BP
Monia
Sanjay
S
Bhanot
D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D051048:Diacylglycerol O-Acyltransferase; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006949:Hyperlipidemias / Q000188:drug therapy*; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D012867:Skin / Q000473:pathology; D014280:Triglycerides / Q000096:biosynthesis
D001786:Blood Glucose; D005227:Fatty Acids; D008055:Lipids; D016376:Oligonucleotides, Antisense; D014280:Triglycerides; D000217:Acyltransferases; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase