Jezek 2015 Antioxid Redox Signal

Ježek J, Dlasková A, Zelenka J, Jabůrek M, Ježek P (2015) H2O2-Activated Mitochondrial Phospholipase iPLA2γ Prevents Lipotoxic Oxidative Stress in Synergy with UCP2, Amplifies Signaling via G-protein-coupled receptor GPR40, and regulates insulin secretion in pancreatic β-cells. Antioxid Redox Signal 23:958-72.

» PMID: 25925080 Open Access

Jezek J, Dlaskova A, Zelenka J, Jaburek M, Jezek P (2015) Antioxid Redox Signal

Abstract: Pancreatic β-cell chronic lipotoxicity evolves from acute free fatty acid (FA)-mediated oxidative stress, unprotected by antioxidant mechanisms. Since mitochondrial uncoupling protein-2 (UCP2) plays antioxidant and insulin-regulating roles in pancreatic β-cells, we tested our hypothesis, that UCP2-mediated uncoupling attenuating mitochondrial superoxide production is initiated by FA release due to a direct H₂O₂-induced activation of mitochondrial phospholipase iPLA₂γ.

Pro-oxidant tert-butylhydroperoxide increased respiration, decreased membrane potential and mitochondrial matrix superoxide release rates of control but not UCP2- or iPLA₂γ-silenced INS-1E cells. iPLA₂γ/UCP2-mediated uncoupling was alternatively activated by an H₂O₂ burst, resulting from palmitic acid (PA) β-oxidation, and it was prevented by antioxidants or catalase overexpression. Exclusively, nascent FAs that cleaved off phospholipids by iPLA₂γ were capable of activating UCP2, indicating that the previously reported direct redox UCP2 activation is actually indirect. Glucose-stimulated insulin release was not affected by UCP2 or iPLA₂γ silencing, unless pro-oxidant activation had taken place. PA augmented insulin secretion via G-protein-coupled receptor 40 (GPR40), stimulated by iPLA₂γ-cleaved FAs (absent after GPR40 silencing). Innovation and Conclusion: The iPLA₂γ/UCP2 synergy provides a feedback antioxidant mechanism preventing oxidative stress by physiological FA intake in pancreatic β-cells, regulating glucose-, FA-, and redox-stimulated insulin secretion. iPLA₂γ is regulated by exogenous FA via β-oxidation causing H₂O₂ signaling, while FAs are cleaved off phospholipids, subsequently acting as amplifying messengers for GPR40. Hence, iPLA₂γ acts in eminent physiological redox signaling, the impairment of which results in the lack of antilipotoxic defense and contributes to chronic lipotoxicity.

• O2k-Network Lab: CZ Prague Jezek P

Labels: MiParea: Respiration 

Stress:Oxidative stress;RONS 

Tissue;cell: Islet cell;pancreas;thymus  Preparation: Permeabilized cells, Isolated mitochondria  Enzyme: Uncoupling protein 

Coupling state: ETS"ETS" is not in the list (LEAK, ROUTINE, OXPHOS, ET) of allowed values for the "Coupling states" property.  Pathway: CIV  HRR: Oxygraph-2k