Oleoyl-lysophosphatidylinositol enhances glucagon-like peptide-1 secretion from enteroendocrine L-cells through GPR119 |
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| Authors: | Syamsul A Arifin Silvano Paternoster Rodrigo Carlessi Ilaria Casari Jeppe Hvidtfeldt Ekberg Tania Maffucci Philip Newsholme Mette M Rosenkilde Marco Falasca |
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| Institution: | 1. Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT London, United Kingdom;2. Department of Basic Medical Science for Nursing, Kulliyyah of Nursing, IIUM, Bandar Indera Mahkota, 25200 Kuantan, Pahang, Malaysia;3. Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia;4. Cell and Molecular Metabolism Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia;5. Laboratory for Molecular Pharmacology, Department for Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark |
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| Abstract: | The gastrointestinal tract is increasingly viewed as critical in controlling glucose metabolism, because of its role in secreting multiple glucoregulatory hormones, such as glucagon like peptide-1 (GLP-1). Here we investigate the molecular pathways behind the GLP-1- and insulin-secreting capabilities of a novel GPR119 agonist, Oleoyl-lysophosphatidylinositol (Oleoyl-LPI). Oleoyl-LPI is the only LPI species able to potently stimulate the release of GLP-1 in vitro, from murine and human L-cells, and ex-vivo from murine colonic primary cell preparations. Here we show that Oleoyl-LPI mediates GLP-1 secretion through GPR119 as this activity is ablated in cells lacking GPR119 and in colonic primary cell preparation from GPR119?/? mice. Similarly, Oleoyl-LPI-mediated insulin secretion is impaired in islets isolated from GPR119?/? mice. On the other hand, GLP-1 secretion is not impaired in cells lacking GPR55 in vitro or in colonic primary cell preparation from GPR55?/? mice. We therefore conclude that GPR119 is the Oleoyl-LPI receptor, upstream of ERK1/2 and cAMP/PKA/CREB pathways, where primarily ERK1/2 is required for GLP-1 secretion, while CREB activation appears dispensable. |
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| Keywords: | GLP-1 glucagon-like peptide-1 GPCR G protein-coupled receptor Oleoyl-LPI Oleoyl-lysophosphatidylinositol T2D type 2 diabetes Lysophosphatidylinositol (LPI) Glucagon-like peptide-1 (GLP-1) GPR119 GPR55 L-cells Mixed colonic preparation |
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