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Insulin and Amino Acid Signaling Through mTOR in Perfused Rat Liver

Insulin and Amino Acid Signaling Through mTOR in Perfused Rat Liver. Jessica Biegler. Objective. Define how amino acids interact with insulin to enhance signaling through mTOR to regulatory mechanisms that control mRNA translation in perfused rat liver. Experimental Design.

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Insulin and Amino Acid Signaling Through mTOR in Perfused Rat Liver

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  1. Insulin and Amino Acid Signaling Through mTOR in Perfused Rat Liver Jessica Biegler

  2. Objective Define how amino acids interact with insulin to enhance signaling through mTOR to regulatory mechanisms that control mRNA translation in perfused rat liver.

  3. Experimental Design • Male, Sprague-Dawley rats 125-150 g • In situ liver perfusion • 20 minute perfusion • Amino acids: 1X or 4X the concentrations found in arterial plasma of a postabsorptive rat • Insulin: 0-, 1-, or 10- nM final concentration • Control: saline perfusion

  4. Traditional Signaling insulin PI3-kinase IRS-1 Akt amino acids ? TSC1 TSC2 ? Rheb hVps34 ? GbL.raptor.mTOR p70S6K1 4E-BP1 rpS6 eIF4E mRNA Translation

  5. Neither Insulin Nor Amino Acids Stimulate a Significant Phosphorylation of IRS-1 on 636/639 N=3

  6. Insulin Stimulates AKT S473 Phosphorylation Independently of Amino Acids N=6

  7. Neither Insulin Nor Amino Acids Stimulate a Significant Association of TSC1/2 N=9

  8. Insulin Stimulates PRAS40 246 Phosphorylation Independently of Amino Acids N=6

  9. Neither Insulin Nor Amino Acids Stimulate a Significant Phosphorylation of TSC1/2 on 1462 N= 9

  10. Neither Insulin Nor Amino Acids Stimulate a Significant Effect on REDD 1 N=6

  11. Neither Insulin Nor Amino Acids Stimulate a Significant Effect on FKBP 38 N=6

  12. Neither Insulin Nor Amino Acids Stimulate a Significant Effect on ATF 4 N=6

  13. Insulin and Amino Acids Stimulate eIF2α Phosphorylation N=6

  14. Insulin and Amino Acids Stimulate a Significant Phosphorylation of mTOR on 2448 N=9

  15. Insulin Nor Amino Acids Stimulate a Significant Association of VPS34 with mTOR N=3

  16. Amino Acids Act Synergistically with Insulin to Enhance Translation Initiation N=9

  17. Amino Acids Act Synergistically with Insulin in the Phosphorylation of eIF4G on 1108 N=6

  18. Amino Acids Act Synergistically with Insulin to Enhance p70 S6K1 Phosphorylation N=9

  19. Amino Acids Act Synergistically with Insulin to Enhance p70 S6K1 Phosphorylation on 389 N=3

  20. Amino Acids are Required for Insulin-Stimulated Protein Synthesis N=9

  21. Proposed Signaling Amino Acids ? ? Insulin eIF2α ATF 4 IRS 1 ? ? mTORC2 PI3K PDK1 REDD 1 ? ? RAG B RAG C ? TSC1 TSC2 PIP2 PIP3 AKT PTEN ? ? PRAS 40 PLD Rheb ? ? ? ? ? mTORC1 FKBP 38 ? S6K1 VPS 34 4E-BP1 eIF4G S6 eIF4E

  22. Conclusions • Amino acids are necessary for insulin-induced signaling through mTOR in perfused rat liver. • Amino acids signaling may be occuring through the association of various proteins with mTOR.

  23. Overall Summary Insulin and amino acids act synergistically to stimulate signaling through mTOR in perfused rat liver. • Vps34/mTOR interaction

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