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...
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Elsevier
2025-01-01
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| Series: | Gastro Hep Advances |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772572324002012 |
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| author | Lili Tian Majid Mufaqam Syed-Abdul Gary F. Lewis |
| author_facet | Lili Tian Majid Mufaqam Syed-Abdul Gary F. Lewis |
| author_sort | Lili Tian |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cd8cf31de9de424588b16bf817a60ea7 |
| institution | OA Journals |
| issn | 2772-5723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Gastro Hep Advances |
| spelling | doaj-art-cd8cf31de9de424588b16bf817a60ea72025-08-20T01:55:52ZengElsevierGastro Hep Advances2772-57232025-01-014410060510.1016/j.gastha.2024.100605Activation of VEGFR3 and MLC2 are Critical for GLP-2 Enhancement of Chylomicron TransportLili Tian0Majid Mufaqam Syed-Abdul1Gary F. Lewis2Division of Endocrinology, Department of Medicine and Physiology, University of Toronto, Toronto, Ontario, CanadaDivision of Endocrinology, Department of Medicine and Physiology, University of Toronto, Toronto, Ontario, CanadaCorrespondence: Address correspondence to: Dr. Gary F. Lewis, MD, Toronto General Hospital, 200 Elizabeth St, EN12-218, Toronto, Ontario M5G2C4, Canada.; Division of Endocrinology, Department of Medicine and Physiology, University of Toronto, Toronto, Ontario, CanadaBackground 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.http://www.sciencedirect.com/science/article/pii/S2772572324002012LymphTriglycerideChylomicronGLP-2 |
| spellingShingle | Lili Tian Majid Mufaqam Syed-Abdul Gary F. Lewis Activation of VEGFR3 and MLC2 are Critical for GLP-2 Enhancement of Chylomicron Transport Gastro Hep Advances Lymph Triglyceride Chylomicron GLP-2 |
| title | Activation of VEGFR3 and MLC2 are Critical for GLP-2 Enhancement of Chylomicron Transport |
| title_full | Activation of VEGFR3 and MLC2 are Critical for GLP-2 Enhancement of Chylomicron Transport |
| title_fullStr | Activation of VEGFR3 and MLC2 are Critical for GLP-2 Enhancement of Chylomicron Transport |
| title_full_unstemmed | Activation of VEGFR3 and MLC2 are Critical for GLP-2 Enhancement of Chylomicron Transport |
| title_short | Activation of VEGFR3 and MLC2 are Critical for GLP-2 Enhancement of Chylomicron Transport |
| title_sort | activation of vegfr3 and mlc2 are critical for glp 2 enhancement of chylomicron transport |
| topic | Lymph Triglyceride Chylomicron GLP-2 |
| url | http://www.sciencedirect.com/science/article/pii/S2772572324002012 |
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