Abstract
Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 catalyzes the final step of triglyceride (TG) synthesis. We show that acute administration of a DGAT1 inhibitor (DGAT1i) by oral gavage or genetic deletion of intestinal Dgat1 (intestine-Dgat1−/−) markedly reduced postprandial plasma TG and retinyl ester excursions by inhibiting chylomicron secretion in mice. Loss of DGAT1 activity did not affect the efficiency of retinol esterification, but it did reduce TG and retinoid accumulation in the small intestine. In contrast, inhibition of microsomal triglyceride transfer protein (MTP) reduced chylomicron secretion after oral fat/retinol loads, but with accumulation of dietary TG and retinoids in the small intestine. Lack of intestinal accumulation of TG and retinoids in DGAT1i-treated or intestine-Dgat1−/− mice resulted, in part, from delayed gastric emptying associated with increased plasma levels of glucagon-like peptide (GLP)-1. However, neither bypassing the stomach through duodenal oil injection nor inhibiting the receptor for GLP-1 normalized postprandial TG or retinyl esters excursions in the absence of DGAT1 activity. In summary, intestinal DGAT1 inhibition or deficiency acutely delayed gastric emptying and inhibited chylomicron secretion; however, the latter occurred when gastric emptying was normal or when lipid was administered directly into the small intestine. Long-term hepatic retinoid metabolism was not impacted by DGAT1 inhibition.
Highlights
Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 catalyzes the final step of triglyceride (TG) synthesis
The seeming discordance between plasma levels of drug and extent of DGAT1 inhibitor (DGAT1i) activity derives from blood concentrations that were greater than the IC50 throughout the 6 h period
At 6 h postgavage, plasma glucagon-like peptide-1 (GLP-1) levels in vehicle- and dirlotapide-treated mice had fallen sharply, while glucagon-like peptide (GLP)-1 levels in DGAT1i-treated mice remained significantly elevated compared with vehicle-treated mice (167%, P < 0.001). These results indicate that the decreases in intestinal and plasma levels of TG and [3H]retinoid observed after DGAT1i treatment may have resulted, at least in part, from delayed gastric emptying caused by prolonged and elevated plasma GLP-1 levels
Summary
Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 catalyzes the final step of triglyceride (TG) synthesis. We show that acute administration of a DGAT1 inhibitor (DGAT1i) by oral gavage or genetic deletion of intestinal Dgat (intestine-Dgat1؊/؊) markedly reduced postprandial plasma TG and retinyl ester excursions by inhibiting chylomicron secretion in mice. Inhibition of microsomal triglyceride transfer protein (MTP) reduced chylomicron secretion after oral fat/retinol loads, but with accumulation of dietary TG and retinoids in the small intestine. Intestinal DGAT1 deficiency reduces postprandial triglyceride and retinyl ester excursions by inhibiting chylomicron secretion and delaying gastric emptying. DGAT1 and DGAT2 are encoded by two genes belonging to different families that do not share significant sequence homology [2,3,4,5] Both genes are ubiquitously expressed but with highest expression levels found in tissues active in TG synthesis, such as adipose tissue, small intestine, liver, and mammary gland. This article is available online at http://www.jlr.org plasma levels over the course of several hours, after oral administration of oil and retinol [11, 16]
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