title: 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.
abstract: 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-N(G)-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.
authors.affiliation: 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; Departments of Biochemistry (J.H., K.E.T., K.A.) and Laboratory Medicine and Pathobiology (S.L.F., J.T., K.A.), University of Toronto, Toronto, Ontario, Canada, M5S 1A8; and State University of New York Downstate Medical Center (J.I., M.H.H.), Brooklyn, New York 11203.
authors.forename: Joanne
authors.initials: J
authors.lastname: Hsieh
authors.affiliation: 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; Departments of Biochemistry (J.H., K.E.T., K.A.) and Laboratory Medicine and Pathobiology (S.L.F., J.T., K.A.), University of Toronto, Toronto, Ontario, Canada, M5S 1A8; and State University of New York Downstate Medical Center (J.I., M.H.H.), Brooklyn, New York 11203.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Trajcevski
authors.affiliation: 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; Departments of Biochemistry (J.H., K.E.T., K.A.) and Laboratory Medicine and Pathobiology (S.L.F., J.T., K.A.), University of Toronto, Toronto, Ontario, Canada, M5S 1A8; and State University of New York Downstate Medical Center (J.I., M.H.H.), Brooklyn, New York 11203.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Farr
authors.affiliation: 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; Departments of Biochemistry (J.H., K.E.T., K.A.) and Laboratory Medicine and Pathobiology (S.L.F., J.T., K.A.), University of Toronto, Toronto, Ontario, Canada, M5S 1A8; and State University of New York Downstate Medical Center (J.I., M.H.H.), Brooklyn, New York 11203.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Baker
authors.affiliation: 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; Departments of Biochemistry (J.H., K.E.T., K.A.) and Laboratory Medicine and Pathobiology (S.L.F., J.T., K.A.), University of Toronto, Toronto, Ontario, Canada, M5S 1A8; and State University of New York Downstate Medical Center (J.I., M.H.H.), Brooklyn, New York 11203.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Lake
authors.affiliation: 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; Departments of Biochemistry (J.H., K.E.T., K.A.) and Laboratory Medicine and Pathobiology (S.L.F., J.T., K.A.), University of Toronto, Toronto, Ontario, Canada, M5S 1A8; and State University of New York Downstate Medical Center (J.I., M.H.H.), Brooklyn, New York 11203.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Taher
authors.affiliation: 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; Departments of Biochemistry (J.H., K.E.T., K.A.) and Laboratory Medicine and Pathobiology (S.L.F., J.T., K.A.), University of Toronto, Toronto, Ontario, Canada, M5S 1A8; and State University of New York Downstate Medical Center (J.I., M.H.H.), Brooklyn, New York 11203.
authors.forename: Jahangir
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: 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; Departments of Biochemistry (J.H., K.E.T., K.A.) and Laboratory Medicine and Pathobiology (S.L.F., J.T., K.A.), University of Toronto, Toronto, Ontario, Canada, M5S 1A8; and State University of New York Downstate Medical Center (J.I., M.H.H.), Brooklyn, New York 11203.
authors.forename: Mahmood M
authors.initials: MM
authors.lastname: Hussain
authors.affiliation: 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; Departments of Biochemistry (J.H., K.E.T., K.A.) and Laboratory Medicine and Pathobiology (S.L.F., J.T., K.A.), University of Toronto, Toronto, Ontario, Canada, M5S 1A8; and State University of New York Downstate Medical Center (J.I., M.H.H.), Brooklyn, New York 11203.
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
mesh_terms: D000818:Animals; D002914:Chylomicrons / Q000378:metabolism*; D006224:Cricetinae; D050171:Dyslipidemias / Q000378:metabolism; D020895:Enterocytes / Q000166:cytology; D053767:Glucagon-Like Peptide 2 / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000737:chemistry; D009569:Nitric Oxide / Q000378:metabolism*; D019518:Postprandial Period; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D002914:Chylomicrons; D053767:Glucagon-Like Peptide 2; D007328:Insulin; D008055:Lipids; D014280:Triglycerides; D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester