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Newly described Anti-Apoptotic Action of Cyclosporine A on Liver Cells: Blockage of Early Changes in Glucose Metabolism


Gottschalk,  S
Department High-Field Magnetic Resonance, Max Planck Institute for Biological Cybernetics, Max Planck Society;

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Gottschalk, S., Raymond V-A, Hohnholt M, Bilodeau, M., & Zwingmann, C. (2006). Newly described Anti-Apoptotic Action of Cyclosporine A on Liver Cells: Blockage of Early Changes in Glucose Metabolism.

We have previously shown that upregulations of specific glucose metabolic pathways are the earliest indicators of Fas receptormediated apoptosis in murine liver. Since cyclosporine A (CsA) is known to prevent apoptosis and has been shown to impair mitochondrial glucose metabolism we hypothesized that CsA could prevent the early increase in glucose metabolism observed in a murine model of hepatocellular apoptosis. BALB/C mice were injected with anti-Fas antibody (0.5 g/g; ip). CsA (50 mg/kg; ip) was injected 45 min prior to anti-Fas. [U-13C]glucose (2.2 mmol/kg; ip) was injected 45 min before sacrifice at several time-points up to 7.5 hours after anti-Fas. Metabolic analysis was carried out on frozen and extracted livers using multinuclear high resolution NMR-spectroscopy. Hepatocyte apoptosis, as evidenced by morphological and biochemical changes such as histological changes, serum-ALT, caspase-3 activity and cleavage of the pro-apoptotic protein BID to its truncated form tBID were not observed until 3 hours after anti-Fas. Fas-mediated apoptosis time-dependently affected several metabolic pathways during the cell death process. Major changes were observed after the onset of hepatocellular injury (7.5 h) such as severe impairment in mitochondrial metabolism as evidenced by a decrease in flux through pyruvate dehydrogenase (PDH: key enzyme for mitochondrial energy metabolism) to 4.9 0.5 of control. In addition metabolic flux via pyruvate carboxylase (PC: anaplerotic enzyme replenishing Krebs cycle intermediates) was also significantly impaired (4.4 1.6 of control). Early after anti-Fas injection, before any evidence of cell injury (1.5 h) we observed enhanced fluxes trough PDH and PC to 224.9 23.3 and 169.5 17.5 of control, respectively. In addition, the de novo synthesis of glutathione (GSH) was increased to 203.0 23.4 of control. Administration of CsA prior to anti-Fas prevented these early changes: mitochondrial glucose metabolism, GSH synthesis and flux trough the anaplerotic pathway (PC) were normalized (81.3 13.6, 107.3 13.9 and 87.7 7.3 of control respectively). CsA treatment also attenuated the late-stage changes mentioned above. We conclude that, in addition to the well-known prevention of the mitochondrial permeability transition, a late event during apoptosis, CsA prevents early stage changes in specific metabolic pathways triggered by Fas-mediated apoptosis. This activity may underlie part of the anti-apoptotic effect of CsA. These studies also show that metabolic activation clearly occurs prior to histopathological evidence of apoptosis and precedes well characterized apoptotic events like BID-cleavage and caspase-3-activation.