tailieunhanh - Báo cáo khoa học: Prohibitin attenuates insulin-stimulated glucose and fatty acid oxidation in adipose tissue by inhibition of pyruvate carboxylase

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. | iFEBS Journal Prohibitin attenuates insulin-stimulated glucose and fatty acid oxidation in adipose tissue by inhibition of pyruvate carboxylase Mahmood Vessal1 Suresh Mishra1 Saby Moulik1 and Liam J. Murphy1 2 1 Physiology Department University of Manitoba Winnipeg Canada 2 InternalMedicine Department University of Manitoba Winnipeg Canada Keywords adipocytes glucose oxidation mitochondria prohibitin pyruvate carboxylase Correspondence L. J. Murphy Room 843 John Buhler Research Centre University of Manitoba Winnipeg Canada Fax 204 789 3940 Tel 204 789 3779 E-mail ljmurph@ Received 4 October 2005 revised 29 November 2005 accepted 6 December 2005 doi 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 w 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. Prohibitin PHB-1 is a multifunctional phylogeneti-cally