No abstract

Prohibitin (PHB‐1) is a highly conserved protein involved in mitochondrial biogenesis and function. It is secreted in lipid droplets from adipocytes and is present in the circulation. In adipose tissue it functions as a membrane receptor and can target binding partners to the mitochondria. Here we report that PHB‐1 has a hitherto undescribed role as an inhibitor of pyruvate carboxylase (PC). As a consequence, it can modulate insulin‐stimulated glucose and fatty acid oxidation. It had no effect on insulin‐stimulated 2‐deoxglucose uptake by isolated adipocytes but inhibited insulin‐stimulated oxidation of [14C]glucose with a half‐maximal concentration of ≈ 4 nm. It also inhibited oleic acid oxidation in glucose‐depleted adipocytes via depletion of oxaloacetate. In vitro experiments using broken‐cell assays confirmed that PHB‐1 inhibited PC. MALDI‐TOF analysis of proteins identified by cross‐linking of PHB‐1 to adipocyte membranes indicated that PHB‐1 is closely associated with PC and EH domain 2 (EHD2). On the basis of these data, we propose that PHB‐1 is recycled between the extracellular space and the mitochondria by a mechanism involving lipid rafts and EHD2 and can modulate mitochondrial fuel metabolism by inhibition of PC.

Our data demonstrates that E + Q plays a protective role against the imbalance elicited by CsA between the production of free radicals and antioxidant defence systems, and suggests that a combination of these two antioxidants may find clinical application where cellular damage is a consequence of ROS.

1. The aim of the present study was to investigate the effects of vitamin E and/or quercetin (Q) on renal function, oxygen radical concentrations in the kidney and some anti-oxidant enzyme activities in rats treated with cyclosporine A (CsA). 2. Groups of rats (270 +/- 15 g), on standard rat chow and water, received all their treatments by gavage for either 4 or 8 weeks. Control groups received either olive oil (0.5 mL) or 25% ethanol (0.5 mL) + olive oil (0.5 mL) per day as vehicle. All experimental groups received 25 mg CsA/kg per day in 0.5 mL olive oil. The vitamin E group received 100 mg vitamin E/kg per day in olive oil in addition to CsA treatment. The quercetin group received 15 mg of Q/kg per day in 0.5 mL of 25% ethanol in addition to CsA treatment. The vitamin E + quercetin group received the two anti-oxidants at the concentrations given in addition to CsA treatment. 3. Quercetin, at a concentration less than one-quarter of vitamin E, was more efficient in lowering blood urea nitrogen, serum creatinine and kidney malondialdehyde in CsA-treated rats. However, neither of the two anti-oxidants was able to normalize these analytes to control values after either 4 or 8 weeks treatment. 4. Quercetin (50 micromol/kg per day) elevated all renal anti-oxidant enzyme activities to values observed in the negative controls. However, vitamin E (232 micromol/kg per day) only normalized glutathione peroxidase activity at the end of either 4 or 8 weeks treatment. Combination treatment with the two anti-oxidants abolished all the ill-effects of CsA. 5. Combination treatment with the two anti-oxidants of renal transplant patients receiving CsA may be beneficial in ameliorating the chronic nephrotoxic effects of the important immunosuppressive drug CsA.

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