Oleoyl-lysophosphatidylinositol enhances glucagon-like peptide-1 secretion from enteroendocrine L-cells through GPR119

Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Sep;1863(9):1132-1141. doi: 10.1016/j.bbalip.2018.06.007. Epub 2018 Jun 5.


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.

Keywords: GPR119; GPR55; Glucagon-like peptide-1 (GLP-1); L-cells; Lysophosphatidylinositol (LPI); Mixed colonic preparation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Enteroendocrine Cells / cytology
  • Enteroendocrine Cells / drug effects*
  • Enteroendocrine Cells / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gene Expression Regulation
  • Glucagon-Like Peptide 1 / genetics*
  • Glucagon-Like Peptide 1 / metabolism
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Lysophospholipids / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Oleic Acids / pharmacology*
  • Primary Cell Culture
  • Receptors, Cannabinoid / deficiency
  • Receptors, Cannabinoid / genetics
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / genetics*
  • Signal Transduction


  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • GPR55 protein, mouse
  • Gpr119 protein, mouse
  • Insulin
  • Lysophospholipids
  • Oleic Acids
  • Receptors, Cannabinoid
  • Receptors, G-Protein-Coupled
  • lysophosphatidylinositol
  • Glucagon-Like Peptide 1
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Mapk1 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3