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

Jul 9, 2013Nature medicine

Blocking Notch reduces liver fat buildup by lowering mTorc1 stability and disconnecting it from Akt activation

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Abstract

Constitutive liver-specific ablation of Notch signaling prevents hepatosteatosis by blocking mTor complex 1 (mTorc1) activity.

Increased hepatic lipid content is associated with insulin resistance and can be triggered by nutrient-induced mTor activation.
Acute or chronic inhibition of Notch signaling reduces hepatic glucose production and may increase Akt activity.
Notch gain of function leads to fatty liver through sustained activation of mTorc1.
Treatment with rapamycin can reverse the fatty liver effect caused by Notch activation.
Notch signaling enhances mTorc1 complex stability, which promotes lipogenesis via the Srebp1c pathway.

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

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