12-Lipoxygenase Products Reduce Insulin Secretion and β-Cell Viability in Human Islets

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 24; no. 2; p. 468
• Main Authors: Ma, K, Nunemaker, C. S, Wu, R, Chakrabarti, S. K, Taylor-Fishwick, D. A, Nadler, J. L
• Format: Journal Article
• Language: English
• Published: Endocrine Society 01.02.2010; Oxford University Press
• Subjects: Translational Highlights from Jcem
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/mend.24.2.9993

ABSTRACT Context Inflammation is increasingly recognized as an important contributing factor in diabetes mellitus. Lipoxygenases (LOs) produce active lipids that promote inflammatory damage by catalyzing the oxidation of linoleic and arachidonic acid, and LO is expressed in rodent and human islets. Little is known about the differential effect of the various hydroxyeicosatetraenoic acids (HETEs) that result from LO activity in human islets. Design We compared the effect of stable compounds derived from LOs: 12(S)-HETE, 15HETE, 12HPETE, and 12RHETE. Interventions At both 1 and 100 nm, insulin secretion was consistently reduced by 12(S)-HETE and 12HPETE. 12(S)-HETE also reduced viability activity by 32% at 1 nm. Insulin and reduced viability were partially reversed by treatment with lisofylline, a small-molecule antiinflammatory compound that protects mitochondrial function. 12(S)-HETE also increased cell death rate of human islets by 50% at 100 nm. To investigate mechanisms of 12-LO-mediated islet inhibition, we examined the p38-MAPK and JNK stress-activated pathways. Results Treatment of 12(S)-HETE significantly increased phosphorylated p38-MAPK (pp38) protein activity in human islets. We further explored the in vivo role of 12-LO in regulating p38-MAPK using mouse models. Knockdown of 12-LO by injecting 12-LO siRNA into C57BL/6 mice decreased pp38 protein levels in mouse islets. The addition of proinflammatory cytokines increased pp38 levels in normal mouse islets but not in siRNA-treated islets. Conclusions These data suggest that 12(S)-HETE reduces insulin secretion and increases cell death in human islets. The 12-LO pathway is present in human islets, and expression is up-regulated by inflammatory cytokines. Reduction of 12-LO activity could thus provide a new therapeutic approach to protect human β-cells from inflammatory injury.