Intestinal DGAT1 deficiency reduces postprandial triglyceride and retinyl
ester excursions by inhibiting chylomicron secretion and delaying gastric
emptying |
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Authors: | Gene P Ables Kryscilla Jian Zhang Yang Silke Vogel Antonio Hernandez-Ono Shuiqing Yu Jason J Yuen Susan Birtles Linda K Buckett Andrew V Turnbull Ira J Goldberg William S Blaner Li-Shin Huang Henry N Ginsberg |
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Institution: | *Department of Medicine, Columbia
University, New York, NY; and;†AstraZeneca R&D, Macclesfield, UK |
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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. |
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Keywords: | diacylglycerol acyltransferase inhibition glucagon-like peptide-1 GLP-1 receptor inhibition lipoproteins retinol absorption |
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