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mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2

Author

Listed:
  • KyeongJin Kim

    (Columbia University)

  • Li Qiang

    (Columbia University)

  • Matthew S. Hayden

    (Columbia University
    Columbia University)

  • David P. Sparling

    (Columbia University)

  • Nicole H. Purcell

    (University of California San Diego)

  • Utpal B. Pajvani

    (Columbia University)

Abstract

Mechanistic target of rapamycin complex 1 (mTORC1), defined by the presence of Raptor, is an evolutionarily conserved and nutrient-sensitive regulator of cellular growth and other metabolic processes. To date, all known functions of Raptor involve its scaffolding mTOR kinase with substrate. Here we report that mTORC1-independent (‘free’) Raptor negatively regulates hepatic Akt activity and lipogenesis. Free Raptor levels in liver decline with age and in obesity; restoration of free Raptor levels reduces liver triglyceride content, through reduced β-TrCP-mediated degradation of the Akt phosphatase, PHLPP2. Commensurately, forced PHLPP2 expression ameliorates hepatic steatosis in diet-induced obese mice. These data suggest that the balance of free and mTORC1-associated Raptor governs hepatic lipid accumulation, and uncover the potentially therapeutic role of PHLPP2 activators in non-alcoholic fatty liver disease.

Suggested Citation

  • KyeongJin Kim & Li Qiang & Matthew S. Hayden & David P. Sparling & Nicole H. Purcell & Utpal B. Pajvani, 2016. "mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2," Nature Communications, Nature, vol. 7(1), pages 1-10, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10255
    DOI: 10.1038/ncomms10255
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