TY - JOUR
T1 - The role of Cox-2 and prostaglandin E2 receptor EP3 in pancreatic b-cell death
AU - Amior, Livnat
AU - Srivastava, Rohit
AU - Nano, Rita
AU - Bertuzzi, Federico
AU - Melloul, Danielle
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Elevated levels of lipids, in particular saturated fatty acids, are known to be associated with type 2 diabetes (T2D) and to have a negative effect on b-cell function and survival. We bring new evidence indicating that palmitate up-regulates cyclooxygenase-2 (COX-2) expression levels in human islets and in MIN6 b cells, and that it is elevated in islets isolated from T2D donors. Both small interfering specific cyclooxygenase-2 small interfering RNA (siRNA) or the COX-2 inhibitor celecoxib significantly inhibited apoptosis induced by palmitate. Prostaglandin E2 (PGE2), the predominant product of COX-2 enzymatic activity, activates membrane receptors, which are members of the GPCR-family (EP1–EP4). In the present study, elevated expression of the PGE2 receptor subtype 3 (EP3) receptor was observed in b cells exposed to palmitate and in islets from individuals with T2D. Down-regulation of the pathway using EP3 siRNA or the specific L-798,106 antagonist markedly decreased the levels of palmitate-induced apoptosis. Altogether, our data put forward the COX-2-PGE2-EP3 pathway as one of the mediators of palmitate-induced apoptosis in b-cells.
AB - Elevated levels of lipids, in particular saturated fatty acids, are known to be associated with type 2 diabetes (T2D) and to have a negative effect on b-cell function and survival. We bring new evidence indicating that palmitate up-regulates cyclooxygenase-2 (COX-2) expression levels in human islets and in MIN6 b cells, and that it is elevated in islets isolated from T2D donors. Both small interfering specific cyclooxygenase-2 small interfering RNA (siRNA) or the COX-2 inhibitor celecoxib significantly inhibited apoptosis induced by palmitate. Prostaglandin E2 (PGE2), the predominant product of COX-2 enzymatic activity, activates membrane receptors, which are members of the GPCR-family (EP1–EP4). In the present study, elevated expression of the PGE2 receptor subtype 3 (EP3) receptor was observed in b cells exposed to palmitate and in islets from individuals with T2D. Down-regulation of the pathway using EP3 siRNA or the specific L-798,106 antagonist markedly decreased the levels of palmitate-induced apoptosis. Altogether, our data put forward the COX-2-PGE2-EP3 pathway as one of the mediators of palmitate-induced apoptosis in b-cells.
KW - Apoptosis
KW - Cyclooxygenase-2
KW - Diabetes mellitus
KW - Islet
KW - Palmitate
UR - http://www.scopus.com/inward/record.url?scp=85064115157&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064115157&partnerID=8YFLogxK
U2 - 10.1096/fj.201801823R
DO - 10.1096/fj.201801823R
M3 - Article
C2 - 30629897
AN - SCOPUS:85064115157
VL - 33
SP - 4975
EP - 4986
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 4
ER -