Intestinal DGAT1 deficiency reduces postprandial triglyceride and retinyl ester excursions by inhibiting chylomicron secretion and delaying gastric emptying.
Intestinal DGAT1 deficiency reduces postprandial triglyceride and retinyl ester excursions by inhibiting chylomicron secretion and delaying gastric emptying.
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DOI：
10.1194/jlr.m029041
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发表时间：
2012-11
影响因子：
6.5
通讯作者：
Ginsberg HN
中科院分区：
文献类型：
--
作者：
Ables GP;Yang KJ;Vogel S;Hernandez-Ono A;Yu S;Yuen JJ;Birtles S;Buckett LK;Turnbull AV;Goldberg IJ;Blaner WS;Huang LS;Ginsberg HN
酰基辅酶a：二酰基甘油酰基转移酶（DGAT） 1催化甘油三酯（TG）合成的最后一步。我们发现，通过口服灌胃或肠道DGAT1基因缺失（intestinal - DGAT1−/−）急性给予DGAT1抑制剂（DGAT1i），通过抑制小鼠乳糜微粒分泌，显著减少餐后血浆TG和视黄醇酯漂移。DGAT1活性的丧失不影响视黄醇酯化的效率，但它确实减少了TG和类视黄醇在小肠中的积累。相比之下，微粒体甘油三酯转移蛋白（MTP）的抑制在口服脂肪/视黄醇负荷后减少了乳糜微粒的分泌，但在小肠中积累了膳食TG和类视黄醇。在dgat1治疗或肠道dgat1 - / -小鼠中，由于胃排空延迟与血浆胰高血糖素样肽(GLP)-1水平升高相关，导致TG和类维生素a缺乏肠道积累。然而，在没有DGAT1活性的情况下，既不能通过十二指肠油注射绕过胃，也不能抑制GLP-1正常化餐后TG或视黄醇酯漂移的受体。综上所述，肠道DGAT1抑制或缺乏严重延迟胃排空并抑制乳糜微粒分泌；然而，后者发生在胃排空正常或脂质直接进入小肠时。长期肝类视黄醇代谢不受DGAT1抑制的影响。
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.