DGAT2 Inhibition Alters Aspects of Triglyceride Metabolism in Rodents but Not in Non-human Primates

Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in triglyceride (TG) synthesis and has been shown to play a role in regulating hepatic very-low-density lipoprotein (VLDL) production in rodents. To explore the potential of DGAT2 as a therapeutic target for the treatment of dyslipidemia, we tested the effects of small-molecule inhibitors and gene silencing both in vitro and in vivo. Consistent with prior reports, chronic inhibition of DGAT2 in a murine model of obesity led to correction of multiple lipid parameters. In contrast, experiments in primary human, rhesus, and cynomolgus hepatocytes demonstrated that selective inhibition of DGAT2 has only a modest effect. Acute and chronic inhibition of DGAT2 in rhesus primates recapitulated the in vitro data yielding no significant effects on production of plasma TG or VLDL apolipoprotein B. These results call into question whether selective inhibition of DGAT2 is sufficient for remediation of dyslipidemia. [Display omitted] •Inhibition of DGAT2 in rodents yields submaximal suppression of VLDL-TG secretion•DGAT1 compensates for loss of DGAT2 activity supporting hepatocyte TG secretion•Inhibition of DGAT2 in rhesus does not affect plasma triglycerides or VLDL-apoB DGAT2 catalyzes the final step in triglyceride synthesis and regulates VLDL production. Using a variety of methods and preclinical models, McLaren et al. show that while DGAT2 inhibition is effective at correcting dyslipidemia in murine models of obesity, these beneficial effects are not translated in vivo in rhesus primates.