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.