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Tiam1/Rac1 signaling pathway mediates palmitate-induced, ceramide-sensitive generation of superoxides and lipid peroxides and the loss of mitochondrial membrane potential in pancreatic beta-cells

, : Tiam1/Rac1 signaling pathway mediates palmitate-induced, ceramide-sensitive generation of superoxides and lipid peroxides and the loss of mitochondrial membrane potential in pancreatic beta-cells. Biochemical Pharmacology 80(6): 874-883

The phagocytic NADPH oxidase [NOX] has been implicated in the generation of superoxides in the pancreatic beta-cell. Herein, using normal rat islets and clonal INS 832/13 cells, we tested the hypothesis that activation of the small G-protein Rac1, which is a member of the NOX holoenzyme, is necessary for palmitate [PA]-induced generation of superoxides in pancreatic beta-cells. Incubation of isolated beta-cells with PA potently increased the NOX activity culminating in a significant increase in the generation of superoxides and lipid peroxides in these cells; such effects of PA were attenuated by diphenyleneiodonium [DPI], a known inhibitor of NOX. In addition, PA caused a transient, but significant activation [i.e., GTP-bound form] of Rac1 in these cells. NSC23766, a selective inhibitor of Rac1, but not Cdc42 or Rho activation, inhibited Rac1 activation and the generation of superoxides and lipid peroxides induced by PA. Fumonisin B-1 [FB-1], which inhibits de novo synthesis of ceramide [CER] from PA, also attenuated PA-induced superoxide and lipid peroxide generation and NOX activity implicating intracellularly generated CER in the metabolic effects of PA; such effects were also demonstrable in the presence of the cell-permeable C2-CER. Further, NSC23766 prevented C2-CER-induced Rac1 activation and production of superoxides and lipid peroxides. Lastly, C2-CER, but not its inactive analogue, significantly reduced the mitochondrial membrane potential, which was prevented to a large degree by NSC23766. Together, our findings suggest that Tiam1/Rac1 signaling pathway regulates PA-induced, CER-dependent superoxide generation and mitochondrial dysfunction in pancreatic beta-cells.


PMID: 20493824

DOI: 10.1016/j.bcp.2010.05.006

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Orr, N.T.; Endean, E.D., 2015: Part Two: Against the Motion. An Endovascular First Strategy is not the Optimal Approach for Treating Acute Mesenteric Ischemia. European Journal of Vascular and Endovascular Surgery 50(3): 276-279

Rhoton F.E.; Meyer L.D.; Whisler F.D., 1982: A laboratory method for predicting the size distribution of sediment eroded from surface soils. A laboratory method was developed to reproduce size distributions of sediment eroded from field plots during simulated rainstorms. Using samples of surface soil from the field plots, sediment size data were generated in the laboratory by agitating...

Molloy, D.P.; Lynn, D.H.; Giamberini, L., 2006: Erratum: Ophryoglena hemophaga n. sp. (Ciliophora: Ophryoglenidae): a parasite of the digestive gland of zebra mussels Dreissena polymorpha (Diseases of Aquatic Organisms 65: 237-243, 2005). Diseases of Aquatic Organisms. June 12; 701-2: 181

Tsai, T-Yow.; Lee, Z-Cheng.; Tsao, H-Xi.; Lin, S-Ting., 2012: Lensless intracavity focusing in a passively Q-switched all-fiber laser using the mode-field-area mismatch. Intense lensless intracavity focusing in a saturable absorber Q-switched all-fiber laser resonator by use of loss arrangement and mode-field-area mismatch between the fibers is investigated for the first time. The intracavity power distribution wa...

Robert J.P.reda; Thure E.C.rling, 1992: Cosmogenic neon in Recent lavas from the Western United States. Geophysical Research Letters 19(18): 1863

Terenius, L., 1973: Estrogen and progestogen binders in human and rat mammary carcinoma. European Journal of Cancer 9(4): 291-294

Santos, L.; Pereira, S.; Criado, B.; Amaro, T.; Bento, M.J.; Guedes Carvalho, R.; Lopes, C., 2001: Molecular cytogenetic analysis of chromosome 7 and 17 and TP53 in bladder cancer A comparative study between young and old patients. Virchows Archiv 439(3): 410, September

Fujimoto, M.; Kotera, K.; Matsumura, Y.; Satake, N.; Honda, M.; Kajino, K.; Naito, K.; Kubota, T., 1979: Cotransport of sodium, HC03- and H+. Nihon Rinsho. Japanese Journal of Clinical Medicine 37(2): 261-267

Rubin P.; Shapiro D.; Finkelstein J.; Penney D.; Gregory P., 1980: Dose effect relationship for surfactant alveolar levels after pulmonary irradiation. Radiation Research 83(2): 381

Maseri, A.; Caldini, P.; Permutt, S.; Zierler, K.L., 1970: Frequency function of transit times through dog pulmonary circulation. Circulation Research 26(5): 527-543