Departments of Medicine and Physiology and Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada.
Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Sep;1867(9):159194. doi: 10.1016/j.bbalip.2022.159194. Epub 2022 Jun 6.
BACKGROUND & AIMS: Dietary triglycerides (TG) retained in the intestine after a meal can be mobilized many hours later by glucagon-like peptide-2 (GLP-2) in humans and animal models, despite the well-documented absence of expression of the GLP-2 receptor on enterocytes. In this study, we examined the site of GLP-2 action to mobilize intestinal lipids and enhance chylomicron production.
In mesenteric lymph duct-cannulated rats, we assessed GLP-2-stimulated lymph flow rate, TG concentration, TG output, and apoB48 abundance 5 h after an intraduodenal lipid bolus, in the presence of a validated GLP-2 antagonist or vehicle. Additionally, the same GLP-2-stimulated parameters were examined in the presence or absence of cis-Golgi disruption by Brefeldin A (BFA).
Compared to placebo, GLP-2 administration increased lymph flow by 2.8-fold (P < 0.001), cumulative lymph volume by 2.69-fold (P < 0.001) and total TG output 2-fold (P = 0.015). GLP-2 receptor antagonism markedly diminished GLP-2's ability to stimulate lymph flow, cumulative lymph volume and total TG output, demonstrating the dependence of GLP-2 stimulation of lymph flow and TG output on its receptor activation. In contrast, disruption of the cis-Golgi apparatus with Brefeldin A did not diminish the GLP-2-response of lymph flow i.e., increased lymph flow by 2.7-fold (P = 0.001), lymph volume by 2.9-fold (P = 0.001), and total TG output i.e., increased by 2.5-fold (P = 0.003).
GLP-2 mobilizes enteral lipid at a site distal to the Golgi, acting via its receptor. Since GLP-2 receptors are not expressed on enterocytes, GLP-2 likely mobilizes intestinal lipid residing extracellularly, either in the lamina propria or in the lymphatics.
尽管已有充分的文献记载表明肠上皮细胞不表达胰高血糖素样肽-2（GLP-2）受体，但在人类和动物模型中，进食后仍有大量甘油三酯（TG）保留在肠道内，数小时后可被 GLP-2 动员。本研究旨在探讨 GLP-2 作用的部位，以动员肠内脂质并增加乳糜微粒的产生。
在肠系膜淋巴管插管大鼠中，我们评估了 GLP-2 刺激后 5 小时内，十二指肠内脂质负荷后，在存在经过验证的 GLP-2 拮抗剂或载体的情况下，GLP-2 刺激对肠道脂肪的动员作用。此外，还通过布雷菲德菌素 A（BFA）来检测 GLP-2 刺激的相同参数，观察顺式高尔基体内的作用。
与安慰剂相比，GLP-2 给药使淋巴流量增加了 2.8 倍（P<0.001），累计淋巴量增加了 2.69 倍（P<0.001），总 TG 输出增加了 2 倍（P=0.015）。GLP-2 受体拮抗剂显著降低了 GLP-2 刺激淋巴流量、累计淋巴量和总 TG 输出的能力，表明 GLP-2 刺激淋巴流量和 TG 输出依赖于其受体的激活。相反，用布雷菲德菌素 A 破坏顺式高尔基器并未降低 GLP-2 对淋巴流量的反应，即增加了 2.7 倍的淋巴流量（P=0.001），增加了 2.9 倍的淋巴量（P=0.001），以及增加了 2.5 倍的总 TG 输出（P=0.003）。
GLP-2 通过其受体在高尔基器远端的部位动员肠内脂质。由于肠上皮细胞不表达 GLP-2 受体，GLP-2 可能动员肠道内位于细胞外的脂质，无论是在固有层还是在淋巴管中。
