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Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability

Abstract

Increased hepatic lipid content is an early correlate of insulin resistance and can be caused by nutrient-induced activation of mammalian target of rapamycin (mTor). This activation of mTor increases basal Akt activity, leading to a self-perpetuating lipogenic cycle. We have previously shown that the developmental Notch pathway has metabolic functions in adult mouse liver. Acute or chronic inhibition of Notch dampens hepatic glucose production and increases Akt activity and may therefore be predicted to increase hepatic lipid content. Here we now show that constitutive liver-specific ablation of Notch signaling, or its acute inhibition with a decoy Notch1 receptor, prevents hepatosteatosis by blocking mTor complex 1 (mTorc1) activity. Conversely, Notch gain of function causes fatty liver through constitutive activation of mTorc1, an effect that is reversible by treatment with rapamycin. We demonstrate that Notch signaling increases mTorc1 complex stability, augmenting mTorc1 function and sterol regulatory element binding transcription factor 1c (Srebp1c)-mediated lipogenesis. These data identify Notch as a therapeutically actionable branch point of metabolic signaling at which Akt activation in the liver can be uncoupled from hepatosteatosis.

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Figure 1: Regulation of hepatic Notch activity.
Figure 2: Lower hepatic triglyceride concentrations in HFD-fed L-Rbpj mice.
Figure 3: Notch1 decoy increases insulin sensitivity and decreases hepatic lipid content.
Figure 4: Activation of hepatic Notch increases mTorc1 activity, lipogenic gene expression and steatosis in chow-fed mice.
Figure 5: mTor inhibition prevents Notch-induced fatty liver.
Figure 6: Notch induces mTorc1 complex stability.

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Acknowledgements

This work was supported by US National Institutes of Health grants DK093604 (U.B.P.), DK57539 (D.A.), HL062454 (J.K.) and DK63608 (Columbia Diabetes Research Center). We thank D. Conlon, C. Eng, I. Goldberg, R. Haeusler and I. Tabas, as well as members of the Accili, Kitajewski and Ginsberg laboratories, for insightful discussion of the data. We acknowledge excellent technical support from A. Flete, T. Kolar and J. Lee, as well as plasmids from D. Sabatini (Whitehead Institute) and B. Spiegelman (Dana-Farber Cancer Institute).

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U.B.P. designed and performed experiments, analyzed data and wrote the manuscript. L.Q. and T.K. designed and performed experiments and analyzed data. J.K., H.N.G. and D.A. designed the studies, analyzed the data and wrote the manuscript.

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Correspondence to Utpal B Pajvani or Domenico Accili.

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Pajvani, U., Qiang, L., Kangsamaksin, T. et al. Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability. Nat Med 19, 1054–1060 (2013). https://doi.org/10.1038/nm.3259

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