title: Knockdown of acyl-CoA:diacylglycerol acyltransferase 2 with antisense oligonucleotide reduces VLDL TG and ApoB secretion in mice.
abstract: Acyl-CoA:diacylglycerol acyltransferases (DGATs) are enzymes that catalyze the formation of triglyceride (TG) from acyl-CoA and diacylglycerol. Two DGATs have been identified which belong to two distinct gene families and both are ubiquitously expressed. DGAT2 knockout mice are lipopenic and die shortly after birth. In the current study, wild type mice were treated with increasing doses (25-60 mg/kg twice weekly) of a DGAT2 gene-specific antisense oligonucleotide (ASO). Treatment resulted in a dose dependent decrease in hepatic DGAT2 gene expression (up to 80%) which was associated with a 40% decrease in hepatic DGAT2 activity and a 45% decrease in hepatic TG. Decreased levels of DGAT2 resulted in a significant dose dependent decrease in VLDL TG secretion (up to 52%) and reduced plasma TG, total cholesterol, and ApoB. Similar results were obtained when DGAT1 KO mice were treated with the DGAT2 ASO. Treatment of ob/ob mice with the DGAT2 ASO resulted in significant decreases in weight gain (10%), adipose weight (25%) and hepatic TG content (80%). Our findings indicate that the majority of TG destined for secretion by liver is synthesized by DGAT2 and suggests that DGAT2 may be a therapeutic target for treatment of hypertriglyceridemia, hepatic steatosis and obesity.
authors.affiliation: Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.forename: Debra A
authors.initials: DA
authors.lastname: Cromley
authors.forename: Mark
authors.initials: M
authors.lastname: Graham
authors.forename: Rosanne
authors.initials: R
authors.lastname: Crooke
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Billheimer
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D051048:Diacylglycerol O-Acyltransferase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008954:Models, Biological; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D001055:Apolipoproteins B; D008055:Lipids; D008079:Lipoproteins, VLDL; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; C516957:DGAT2 protein, mouse; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase