Open AccessPotential mechanism of enhanced postprandial glucagon‐like peptide‐1 release following treatment with a diacylglycerol acyltransferase 1 inhibitor
Author(s) -
Liu Jinqi,
McLaren David G.,
Chen Dunlu,
Kan Yanqing,
Stout Steven J.,
Shen Xiaolan,
Murphy Beth Ann,
Forrest Gail,
Karanam Bindhu,
Sonatore Lisa,
He Shuwen,
Roddy Thomas P.,
Pinto Shirly
Publication year - 2015
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.193
Subject(s) - postprandial , chemistry , diacylglycerol kinase , medicine , meal , endocrinology , small intestine , biochemistry , pharmacology , biology , food science , enzyme , protein kinase c , insulin
Studies have demonstrated that blockade of diacylglycerol acyltransferase 1 ( DGAT 1) leads to prolonged release of glucagon‐like peptide 1 ( GLP ‐1) after meal challenge. The current study was undertaken to investigate the mechanism of action underlying the elevated levels of GLP ‐1 release following pharmacological inhibition of DGAT 1. We utilized a potent, specific DGAT 1 inhibitor, compound A , to investigate the changes in intestinal lipid profile in a mouse model after oral administration of the compound and challenge with tracer containing fatty meal. [ 13 C 18 ]‐oleic acid and LC ‐ MS were employed to trace the fate of dietary fatty acids provided as part of a meal challenge in lean mice. Lipid profiles in plasma, proximal to distal segments of intestine, and feces were evaluated at various times following the meal challenge to study the kinetics of fatty acid absorption, synthesis into complex lipids, and excretion. Pharmacological inhibition of DGAT 1 led to reduction of postprandial total and newly synthesized triglyceride ( TG ) excursion and significant increases in TG and FFA levels in the distal portion of intestine enriched with enteroendocrine L cells. Enhanced levels of FFA and cholesteryl ester were observed via fecal fat profiling. DGAT 1 inhibition leads to enhancement of carbon flow to the synthesis of phosphatidylcholine within the intestine. DGAT 1 inhibition markedly increases levels of TG and FFA in the distal intestine, which could be the predominant contributor to the prolonged and enhanced postprandial GLP ‐1 release. Inactivation of DGAT 1 could provide potential benefit in the treatment of dysmetabolic diseases.