A 12-lipoxygenase-Gpr31 signaling axis is required for pancreatic organogenesis in the zebrafish.
12-lipoxygenase
Gpr31
exocrine tissue
pancreas development
zebrafish
β cells
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
11
09
2019
revised:
21
08
2020
accepted:
25
08
2020
pubmed:
13
9
2020
medline:
1
5
2021
entrez:
12
9
2020
Statut:
ppublish
Résumé
12-Lipoxygenase (12-LOX) is a key enzyme in arachidonic acid metabolism, and alongside its major product, 12-HETE, plays a key role in promoting inflammatory signaling during diabetes pathogenesis. Although 12-LOX is a proposed therapeutic target to protect pancreatic islets in the setting of diabetes, little is known about the consequences of blocking its enzymatic activity during embryonic development. Here, we have leveraged the strengths of the zebrafish-genetic manipulation and pharmacologic inhibition-to interrogate the role of 12-LOX in pancreatic development. Lipidomics analysis during zebrafish development demonstrated that 12-LOX-generated metabolites of arachidonic acid increase sharply during organogenesis stages, and that this increase is blocked by morpholino-directed depletion of 12-LOX. Furthermore, we found that either depletion or inhibition of 12-LOX impairs both exocrine pancreas growth and unexpectedly, the generation of insulin-producing β cells. We demonstrate that morpholino-mediated knockdown of GPR31, a purported G-protein-coupled receptor for 12-HETE, largely phenocopies both the depletion and the inhibition of 12-LOX. Moreover, we show that loss of GPR31 impairs pancreatic bud fusion and pancreatic duct morphogenesis. Together, these data provide new insight into the requirement of 12-LOX in pancreatic organogenesis and islet formation, and additionally provide evidence that its effects are mediated via a signaling axis that includes the 12-HETE receptor GPR31.
Identifiants
pubmed: 32918516
doi: 10.1096/fj.201902308RR
pmc: PMC7606739
mid: NIHMS1634728
doi:
Substances chimiques
Receptors, G-Protein-Coupled
0
Zebrafish Proteins
0
Arachidonic Acid
27YG812J1I
Lipoxygenases
EC 1.13.11.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
14850-14862Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK060581
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK064466
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK097512
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK105588
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020579
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020595
Pays : United States
Organisme : NCATS NIH HHS
ID : R03 TR003381
Pays : United States
Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
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