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

UB Pajvani, L Qiang, T Kangsamaksin, J Kitajewski… - Nature medicine, 2013 - nature.com
Nature medicine, 2013nature.com
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 …
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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