Glucagon-Like Peptide 2 (GLP-2) Stimulates Postprandial Chylomicron Production and Postabsorptive Release of Intestinal Triglyceride Storage Pools via Induction of Nitric Oxide Signaling in Male Hamsters and Mice
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- Joanne Hsieh
- Molecular Structure and Function (J.H., K.E.T., S.L.F., C.L.B., E.J.L., J.T., K.A.), Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8
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- Karin E. Trajcevski
- Molecular Structure and Function (J.H., K.E.T., S.L.F., C.L.B., E.J.L., J.T., K.A.), Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8
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- Sarah L. Farr
- Molecular Structure and Function (J.H., K.E.T., S.L.F., C.L.B., E.J.L., J.T., K.A.), Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8
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- Christopher L. Baker
- Molecular Structure and Function (J.H., K.E.T., S.L.F., C.L.B., E.J.L., J.T., K.A.), Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8
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- Elizabeth J. Lake
- Molecular Structure and Function (J.H., K.E.T., S.L.F., C.L.B., E.J.L., J.T., K.A.), Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8
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- Jennifer Taher
- Molecular Structure and Function (J.H., K.E.T., S.L.F., C.L.B., E.J.L., J.T., K.A.), Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8
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- Jahangir Iqbal
- State University of New York Downstate Medical Center (J.I., M.H.H.), Brooklyn, New York 11203
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- Mahmood M. Hussain
- State University of New York Downstate Medical Center (J.I., M.H.H.), Brooklyn, New York 11203
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- Khosrow Adeli
- Molecular Structure and Function (J.H., K.E.T., S.L.F., C.L.B., E.J.L., J.T., K.A.), Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8
抄録
<jats:p>The intestinal overproduction of apolipoprotein B48 (apoB48)-containing chylomicron particles is a common feature of diabetic dyslipidemia and contributes to cardiovascular risk in insulin resistant states. We previously reported that glucagon-like peptide-2 (GLP-2) is a key endocrine stimulator of enterocyte fat absorption and chylomicron output in the postprandial state. GLP-2's stimulatory effect on chylomicron production in the postabsorptive state has been confirmed in human studies. The mechanism by which GLP-2 regulates chylomicron production is unclear, because its receptor is not expressed on enterocytes. We provide evidence for a key role of nitric oxide (NO) in mediating the stimulatory effects of GLP-2 during the postprandial and postabsorptive periods. Intestinal chylomicron production was assessed in GLP-2-treated hamsters administered the pan-specific NO synthase (NOS) inhibitor L-NG-nitroarginine methyl ester (L-NAME), and in GLP-2-treated endothelial NOS knockout mice. L-NAME blocked GLP-2-stimulated apoB48 secretion and reduced triglycerides (TGs) in the TG-rich lipoprotein (TRL) fraction of the plasma in the postprandial state. Endothelial NOS-deficient mice were resistant to GLP-2 stimulation and secreted fewer large apoB48-particles. When TG storage pools were allowed to accumulate, L-NAME mitigated the GLP-2-mediated increase in TRL-TG, suggesting that NO is required for early mobilization and secretion of stored TG and preformed chylomicrons. Importantly, the NO donor S-nitroso-L-glutathione was able to elicit an increase in TRL-TG in vivo and stimulate chylomicron release in vitro in primary enterocytes. We describe a novel role for GLP-2-mediated NO-signaling as a critical regulator of intestinal lipid handling and a potential contributor to postprandial dyslipidemia.</jats:p>
収録刊行物
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- Endocrinology
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Endocrinology 156 (10), 3538-3547, 2015-07-01
The Endocrine Society