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DGAT2 Inhibition Doesn’t Affect Plasma Triglycerides, VLDL ApoB

by Judith Gorski PhD, June 19, 2018 at 01:00 PM | Tags

DGAT2 inhibitors, dyslipidemia, low density lipoprotein binding on cell membrane

DGAT2 inhibitors, dyslipidemia, low density lipoprotein binding on cell membraneIn a new study published in Cell Metabolism, McClaren et al utilize a variety of translational models, including both mouse models and non-human primate (NHP) models of obesity, to explore a potential therapeutic target for dyslipidemia. Their study focused on the effects of DGAT2 inhibition on lipid metabolism and whole-body metabolic flux.

Diacylglycerol acyltransferase (DGAT) catalyzes the final reaction of triacylgycerol synthesis and has been implicated in the regulation of hepatic very-low-density lipoprotein (VLDL) production in rodents.

Reducing Dyslipidemia via Inhibition of Triglyceride Synthesis

Patients with type 2 diabetes have a higher risk of cardiovascular arterial disease. Diabetic dyslipidemia increases the risk of atherosclerosis occurring in this patient population and is characterized by increased plasma triglycerides (TG) and insulin resistance. It has been hypothesized that blocking TG synthesis could help correct dyslipidemia, due to downstream outcomes including decreasing apolipoprotein B (ApoB) release and a reduction in the number of LDL circulating particles.

Significant Adverse Events with DGAT1 Inhibitors

The final step in the synthesis of TG is catalyzed by DGAT, of which there are two reported isozymes: DGAT1 and DGAT2. DGAT1 deletion in rodents has multiple beneficial effects with obesity and diabetes phenotypes, primarily via alteration of lipid absorption and incretin release. Given these findings, DGAT1i’s seemed like a promising therapeutic target - until significant adverse effects related to GI intolerability were found.

Beneficial Effects of DGAT2 Inhibition

Contrary to the beneficial knockout effects of DGAT1, DGAT2 was found to be lethal, and DGAT2 knockout mice die shortly after birth. Despite this perinatal phenotype, Choi et al used anti-oligonucleotides (ASO) in rodents to demonstrate beneficial effects, such as reductions in liver steatosis, plasma insulin, and triglycerides. This data supported development of DGAT2 inhibitors as potential therapeutics and suggested further study in rodent and NHP models.

DGAT2 Inhibition in Rodent and NHP Preclinical Models

The authors first showed robust TG alteration in rodents with DGAT2 inhibition, which proved effective in correcting dyslipidemia in mouse models of obesity. Next, they evaluated DGAT2 inhibition in a more translationally-relevant NHP model to assess its value as a therapeutic target.

A short-term fructose-fed rhesus primate model proved to be appropriately responsive to manipulations known to affect VLDL-TG secretion. Feeding rhesus fructose for three consecutive days changed the metabolic status of the animals, including elevated insulin, TG, and VLDL ApoB synthesis.

Newly synthesized TG 54:3 in Rhesus after 3 Days of Fructose Treatment
McLaren et al. Cell Metab 2018;27(6):1236-1248.e6

Administration of lomipatide (an MTP inhibitor approved for treating familial hypocholesteremia and improving metabolic function) showed reductions in TG similar to those observed in humans. Recapitulation of MTP inhibition in this rhesus model suggests sensitivity to detect significant changes in TG and VLDL ApoB synthesis and validates this as a reliable model for assessing the effects of DGAT2 inhibition.

Reduction of Plasma Concentration of TG 54:3 Labeled with [2H5] Glycerol
over the 4-Hour Period after a Single Dose of MTP Inhibitor

McLaren et al. Cell Metab 2018;27(6):1236-1248.e6

DGAT2 Inhibition Not Effective in this NHP Model

The results obtained show effective translation from in vitro to in vivo experiments. However, they showed that the prolonged knock down of DGAT2 (comparable to the rodent studies) did not result in significant reduction in plasma TG in the rhesus, highlighting species to species differences in the role of DGAT2. These results lead the authors to question whether selective inhibition of DGAT2 is sufficient for remediation of dyslipidemia.


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