Jezek 2015 Antioxid Redox Signal

From Bioblast
Publications in the MiPMap
JeΕΎek J, DlaskovΓ‘ A, Zelenka J, JabΕ―rek M, JeΕΎek P (2015) H2O2-activated mitochondrial phospholipase iPLA2Ξ³ prevents lipotoxic oxidative stress in synergy with UCP2, amplifies signaling via G-protein-coupled receptor GPR40, and regulates insulin secretion in pancreatic Ξ²-cells. Antioxid Redox Signal 23:958-72.

Β» PMID: 25925080 Open Access

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

Abstract: Pancreatic Ξ²-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 Ξ²-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 iPLA2Ξ³.

Pro-oxidant tert-butylhydroperoxide increased respiration, decreased membrane potential and mitochondrial matrix superoxide release rates of control but not UCP2- or iPLA2Ξ³-silenced INS-1E cells. iPLA2Ξ³/UCP2-mediated uncoupling was alternatively activated by an H2O2 burst, resulting from palmitic acid (PA) Ξ²-oxidation, and it was prevented by antioxidants or catalase overexpression. Exclusively, nascent FAs that cleaved off phospholipids by iPLA2Ξ³ 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 iPLA2Ξ³ silencing, unless pro-oxidant activation had taken place. PA augmented insulin secretion via G-protein-coupled receptor 40 (GPR40), stimulated by iPLA2Ξ³-cleaved FAs (absent after GPR40 silencing). Innovation and Conclusion: The iPLA2Ξ³/UCP2 synergy provides a feedback antioxidant mechanism preventing oxidative stress by physiological FA intake in pancreatic Ξ²-cells, regulating glucose-, FA-, and redox-stimulated insulin secretion. iPLA2Ξ³ is regulated by exogenous FA via Ξ²-oxidation causing H2O2 signaling, while FAs are cleaved off phospholipids, subsequently acting as amplifying messengers for GPR40. Hence, iPLA2Ξ³ acts in eminent physiological redox signaling, the impairment of which results in the lack of antilipotoxic defense and contributes to chronic lipotoxicity.

β€’ 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: ET  Pathway: CIV  HRR: Oxygraph-2k 

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