Intestinal DGAT1 deficiency reduces postprandial triglyceride and retinyl ester excursions by inhibiting chylomicron secretion and delaying gastric emptying

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.

Intestine-specific expression of MOGAT2 partially restores metabolic efficiency in Mogat2-deficient mice

“…MGAT2 is the major contributor of MGAT activity in the intestine ( 8,12 ). MGAT activity in vitro and the ability to incorporate monoacylglycerol into triacylglycerol were signifi cantly reduced in the intestine gain induced by high-fat feeding have been reported in rodents (35)(36)(37). Whether some of the inhibitors are efficacious therapeutic agents for metabolic diseases in humans remains to be determined.…”

“…Glucosyl units released in both groups were measured using a colorimetric glucose kit (Wako Diagnostics). The nonhydrolyzed group represented the free glucose measurement, while the difference between the hydrolyzed by guest, on May 9, 2018 www.jlr.org activity, such as acyl CoA:diacylglycerol acyltransferase (DGAT)1 ( 26 ), which are highly expressed in the intestine. In contrast, M2…”

Novel role of a triglyceride-synthesizing enzyme: DGAT1 at the crossroad between triglyceride and cholesterol metabolism

“…However, whether cholesterol concentrations and cholesterol metabolism per se are altered upon intestinal or systemic DGAT1 deficiency have not been explored. In the current study, we found that secretion of post-prandial [8]. DGAT1 possesses acyl-CoA:retinol acyltransferase activity [28], which could partly explain the reduction in chylomicron retinyl ester excursion due to intestinal DGAT1 deficiency.…”

“…Chylomicron secretion rate using [9, H(N)]triolein (Perkin Elmer, Boston, MA) and [ 14 C]cholesterol (ARC Inc., St. Louis, MO) was assessed as previously described [8] with minor modifications. Briefly, mice fed HF/HCD for 12 weeks were fasted for 4 h starting at 6 a.m.…”

Usefulness of Obese Animal Models in Antiobesity Drug Development

“…Repeated administration of JTT-553 showed decreases of the liver and fat weights, and the liver TG content. The DGAT1 inhibitor was considered to suppress food consumption via the elevation of levels of gut hormones, such as GLP-1, in plasma [99]. Furthermore, JTT-553 was administrated to DIO mice and antiobesity effects and antidiabetic effects were investigated at the same time [98].…”