Metabolic regulation by leucine of translation initiation through the mTOR-signaling pathway by pancreatic beta-cells.

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155

作者：

G Xu，G Kwon，Wilhelm S.Cruz

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摘要：

Recent findings have demonstrated that the branched-chain amino acidleucine can activate the translational regulators, phosphorylated heat- andacid-stable protein regulated by insulin (PHAS-I) and p70 S6 kinase(p70s6k), in an insulin-independent and rapamycin-sensitive mannerthrough mammalian target of rapamycin (mTOR), although the mechanism for thisactivation is undefined. It has been previously established thatleucine-induced insulin secretion by β-cells involves increasedmitochondrial metabolism by oxidative decarboxylation and allostericactivation of glutamate dehydrogenase (GDH). We now show that these sameintramitochondrial events that generate signals for leucine-induced insulinexocytosis are required to activate the mTOR mitogenic signaling pathway byβ-cells. Thus, a minimal model consisting of leucine and glutamine assubstrates for oxidative decarboxylation and an activator of GDH,respectively, confirmed the requirement for these two metabolic components andmimicked closely the synergistic interactions achieved by a completecomplement of amino acids to activate p70s6k in arapamycin-sensitive manner. Studies using various leucine analogs alsoconfirmed the close association of mitochondrial metabolism and the ability ofleucine analogs to activate p70s6k. Furthermore, selectiveinhibitors of mitochondrial function blocked this activation in a reversiblemanner, which was not associated with a global reduction in ATP levels. Thesefindings indicate that leucine at physiological concentrations stimulatesp70s6k phosphorylation via the mTOR pathway, in part, by servingboth as a mitochondrial fuel and an allosteric activator of GDH.Leucine-mediated activation of protein translation through mTOR may contributeto enhanced β-cell function by stimulating growth-related proteinsynthesis and proliferation associated with the maintenance of β-cellmass.

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关键词：

Islets of Langerhans Cell Line Mitochondria Glutamate Dehydrogenase Phosphotransferases (Alcohol Group Acceptor Protein Kinases Ribosomal Protein S6 Kinases Glutamic Acid Isoleucine Leucine