Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance.
Nonalcoholic fatty liver disease (NAFLD) is a major contributing factor to hepatic insulin resistance in type 2 diabetes. Diacylglycerol acyltransferase (Dgat), of which there are two isoforms (Dgat1 and Dgat2), catalyzes the final step in triglyceride synthesis. We evaluated the metabolic impact of pharmacological reduction of DGAT1 and -2 expression in liver and fat using antisense oligonucleotides (ASOs) in rats with diet-induced NAFLD. Dgat1 and Dgat2 ASO treatment selectively reduced DGAT1 and DGAT2 mRNA levels in liver and fat, but only Dgat2 ASO treatment significantly reduced hepatic lipids (diacylglycerol and triglyceride but not long chain acyl CoAs) and improved hepatic insulin sensitivity. Because Dgat catalyzes triglyceride synthesis from diacylglycerol, and because we have hypothesized that diacylglycerol accumulation triggers fat-induced hepatic insulin resistance through protein kinase C epsilon activation, we next sought to understand the paradoxical reduction in diacylglycerol in Dgat2 ASO-treated rats. Within 3 days of starting Dgat2 ASO therapy in high fat-fed rats, plasma fatty acids increased, whereas hepatic lysophosphatidic acid and diacylglycerol levels were similar to those of control rats. These changes were associated with reduced expression of lipogenic genes (SREBP1c, ACC1, SCD1, and mtGPAT) and increased expression of oxidative/thermogenic genes (CPT1 and UCP2). Taken together, these data suggest that knocking down Dgat2 protects against fat-induced hepatic insulin resistance by paradoxically lowering hepatic diacylglycerol content and protein kinase C epsilon activation through decreased SREBP1c-mediated lipogenesis and increased hepatic fatty acid oxidation.
Choi
Cheol Soo
CS
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Savage
David B
DB
Kulkarni
Ameya
A
Yu
Xing Xian
XX
Liu
Zhen-Xiang
ZX
Morino
Katsutaro
K
Kim
Sheene
S
Distefano
Alberto
A
Samuel
Varman T
VT
Neschen
Susanne
S
Zhang
Dongyan
D
Wang
Amy
A
Zhang
Xian-Man
XM
Kahn
Mario
M
Cline
Gary W
GW
Pandey
Sanjay K
SK
Geisler
John G
JG
Bhanot
Sanjay
S
Monia
Brett P
BP
Shulman
Gerald I
GI
D000818:Animals; D051048:Diacylglycerol O-Acyltransferase / Q000378:metabolism / Q000502:physiology*; D004032:Diet; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000473:pathology* / Q000628:therapy; D022781:Hepatocytes / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism
D005227:Fatty Acids; D016376:Oligonucleotides, Antisense; D014280:Triglycerides; C494883:Dgat1 protein, rat; C522579:Dgat2 protein, rat; D051048:Diacylglycerol O-Acyltransferase; D010100:Oxygen