VEGFR3和MLC2的激活是GLP-2增强乳糜微粒运输的关键

Gastro hep advances Pub Date : 2025-01-01 DOI:10.1016/j.gastha.2024.100605

Lili Tian , Majid Mufaqam Syed-Abdul , Gary F. Lewis

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引用次数: 0

摘要

背景和目的：在脂肪摄入后，大量吸收的膳食甘油三酯（tg）在细胞内和细胞外的各个肠室中停留数小时，包括在淋巴循环中。保留在肠道或淋巴管中的tg可被胰高血糖素样肽2 （GLP-2）和其他刺激调动。我们之前发表的数据表明，GLP-2通过作用于远端肠细胞，特别是通过增强乳管收缩性，以肠神经系统依赖的方式增强淋巴流动。本研究的目的是进一步探索GLP-2促进肠系膜淋巴流动的信号通路中的各种中间体。在这项研究中，我们重点关注血管内皮生长因子受体3 （VEGFR3）和肌球蛋白轻链2 （MLC2）的作用，已知它们分别在淋巴管生成和淋巴收缩中起重要作用。方法采用大鼠淋巴瘘模型。在以下腹腔（i.p）给药前5小时给予大鼠腹腔内脂质丸：1)生理盐水（安慰剂），2)GLP-2, 3) GLP-2 + MAZ-51（一种VEGFR3抑制剂），4)GLP-2 + SAR131675（第二种VEGFR3抑制剂），5)GLP-2 + ML-7（一种MLCK抑制剂）。在给药后60分钟评估淋巴流量和TG输出。在另一组动物中，p后。收集组织样本，量化VEGFR3和MLC2的激活（通过磷酸化）。结果我们发现，GLP-2治疗可急性激活VEGFR3和MLC2，抑制VEGFR3（通过MAZ-51/SAR131675）和MLC2（通过ML-7）可消除GLP-2诱导的淋巴流动和TG输出。此外，VEGFR3抑制抑制了MLC2的激活。结论我们的数据表明，VEGFR3和MLC2的激活在GLP-2增强乳糜微粒分泌中起关键作用，VEGFR3的激活是GLP-2激活MLC2的重要中间步骤。

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Activation of VEGFR3 and MLC2 are Critical for GLP-2 Enhancement of Chylomicron Transport

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Activation of VEGFR3 and MLC2 are Critical for GLP-2 Enhancement of Chylomicron Transport

Background and Aims

A significant proportion of absorbed dietary triglycerides (TGs) remain in various intracellular and extracellular intestinal compartments for many hours after fat ingestion, including in the lymphatic circulation. TGs retained in the intestine or lymphatics can be mobilized by the gut peptide glucagon-like peptide 2 (GLP-2) and other stimuli. Our previous published data demonstrated that GLP-2 enhances lymph flow by acting distal to the enterocyte, specifically by enhancing lacteal contractility, in an enteric nervous system–dependent fashion. The objective of the present study was to further explore various intermediates in the signaling pathway whereby GLP-2 enhances mesenteric lymph flow. In this study we focused on the roles of vascular endothelial growth factor receptor 3 (VEGFR3) and myosin light chain 2 (MLC2), known to play important roles in lymphangiogenesis and lymphatic contractility, respectively.

Methods

A rat lymph fistula model was utilized in this study. An intraduodenal lipid bolus was applied to the rats 5 hours before the following intraperitoneal (i.p.) administrations: 1) saline (placebo), 2) GLP-2, 3) GLP-2 + MAZ-51 (a VEGFR3 inhibitor), 4) GLP-2 + SAR131675 (a second VEGFR3 inhibitor), 5) GLP-2 + ML-7 (a MLCK inhibitor). Lymph flow and TG output were assessed for 60 minutes after the i.p. administrations. In another set of animals, post-i.p. administration, tissue samples were collected to quantify VEGFR3 and MLC2 activation (via phosphorylation).

Results

We showed that GLP-2 treatment acutely activated VEGFR3 and MLC2, and that inhibition of VEGFR3 (via MAZ-51/SAR131675) and MLC2 (via ML-7) abolished GLP-2-induced lymph flow and TG output. Furthermore, VEGFR3 inhibition blocked MLC2 activation.

Conclusion

Our data suggest that the activation of VEGFR3 and MLC2 play critical roles in GLP-2’s enhancement of chylomicron secretion and that VEGFR3 activation is an important intermediary step in GLP-2’s activation of MLC2.

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来源期刊

Gastro hep advances Gastroenterology

CiteScore

0.80

自引率

0.00%

发文量

审稿时长

64 days