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12‐HETE Signaling Through the G Protein‐Coupled Receptor 31 (GPR31) Regulates Pancreas Development and Disease
Author(s) -
Anderson Ryan Mallory,
HernandezPerez Marimar,
Tersey Sarah,
Samala Niharika,
Maier Bernhard,
Mirmira Raghavendra G.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb503
Subject(s) - inflammation , pancreatic islets , endocrinology , biology , medicine , islet , lipid signaling , signal transduction , gene knockdown , integrated stress response , zebrafish , microbiology and biotechnology , receptor , unfolded protein response , immunology , diabetes mellitus , apoptosis , endoplasmic reticulum , biochemistry , translation (biology) , messenger rna , gene
Inflammation is essential for pathogen defense and tissue repair, but drives many pathologies when dysregulated. For instance, inflammation plays a critical role in pancreatic β cell dysfunction, and is a hallmark of both type 1 and type 2 diabetes. Thus, the molecular pathways initiating and escalating islet inflammation are prime targets for novel diabetes therapeutics. One such inflammatory mediator, 12‐hydroxyeicosatetraenoic acid (12‐HETE), is an oxygenated derivative of arachidonic acid generated by 12‐Lipoxygenase (12‐LO). Pancreatic deletion of 12‐LO protects obese high fat diet‐fed mice from glucose intolerance, and improves insulin secretion in cytokine‐treated islets in a 12‐HETE‐dependent manner. In vitro assays have shown that 12‐HETE can ligate the G protein coupled receptor GPR31, but little is known about the activation of this pathway or its role in islet biology; we hypothesized that the pancreatic actions of 12‐HETE are mediated in part by GPR31. Accordingly, when the beta cell line βTC3 was treated with 12‐HETE, we measured an induction of ER stress markers and suppression of oxidative stress pathway markers; these effects were blocked by shRNA knockdown of Gpr31 , suggesting that 12‐HETE/GPR31 signaling is a node of convergence for stress pathways during inflammatory response in mouse β cells. To further clarify the in vivo roles of this pathway, we generated loss‐of function zebrafish models for both 12‐lipoxygenase ( alox12 ) and gpr31 using morpholinos and CRISPR/Cas9. Loss of alox12 diminished 12‐HETE production and unexpectedly impaired pancreatic growth. Similarly, the loss of gpr31 resulted in a severe reduction of pancreas tissues via impaired differentiation. We propose that 12‐HETE signaling via GPR31 is an important paracrine and/or autocrine pathway involved in diabetes pathogenesis that is also essential for pancreas formation during development. Support or Funding Information This work is supported by NIDDK grant R01 DK105588 02 to RM