Intestinal DGAT1 deficiency reduces postprandial triglyceride and retinyl ester excursions by inhibiting chylomicron secretion and delaying gastric emptying.
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.
Department of Medicine, Columbia University, New York, NY, USA.
Gene P
GP
Ables
Kryscilla Jian Zhang
KJ
Yang
Silke
S
Vogel
Antonio
A
Hernandez-Ono
Shuiqing
S
Yu
Jason J
JJ
Yuen
Susan
S
Birtles
Linda K
LK
Buckett
Andrew V
AV
Turnbull
Ira J
IJ
Goldberg
William S
WS
Blaner
Li-Shin
LS
Huang
Henry N
HN
Ginsberg
D000818:Animals; D002219:Carbamates / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002914:Chylomicrons / Q000378:metabolism*; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D005746:Gastric Emptying / Q000187:drug effects / Q000235:genetics*; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D000067757:Glucagon-Like Peptide-1 Receptor; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010446:Peptide Fragments / Q000494:pharmacology; D019518:Postprandial Period / Q000235:genetics / Q000502:physiology*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors; D012176:Retinoids / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
D002219:Carbamates; D002352:Carrier Proteins; D002914:Chylomicrons; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007211:Indoles; D010446:Peptide Fragments; D018027:Receptors, Glucagon; D012176:Retinoids; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; C083773:exendin (9-39); C521290:dirlotapide; D052216:Glucagon-Like Peptide 1; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase