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

Utpal B Pajvani1, Li Qiang, Thaned Kangsamaksin

  • 1Department of Medicine, Columbia University, New York, New York, USA. up2104@columbia.edu

Nature Medicine
|July 9, 2013
PubMed

Insights

Notch signaling drives liver fat accumulation by activating mTORC1 and lipogenesis. Inhibiting Notch prevents and reverses fatty liver disease, offering a therapeutic target for metabolic dysfunction.

Area of Science:

  • Metabolic signaling pathways
  • Hepatology
  • Molecular mechanisms of liver disease

Background:

  • Hepatic lipid accumulation is linked to insulin resistance and nutrient-induced mammalian target of rapamycin (mTOR) activation.
  • The Notch pathway, known for developmental roles, also influences adult liver metabolism.
  • Previous work suggested Notch inhibition might increase hepatic lipid content due to enhanced Akt activity.

Purpose of the Study:

  • To investigate the role of Notch signaling in regulating hepatic lipid content and its connection to mTOR.
  • To determine if Notch signaling directly impacts hepatosteatosis (fatty liver disease).
  • To explore Notch as a potential therapeutic target for metabolic liver diseases.

Main Methods:

  • Constitutive liver-specific ablation of Notch signaling in mice.
  • Acute inhibition of Notch signaling using a decoy Notch1 receptor.
  • Assessment of mTOR complex 1 (mTORC1) activity, Akt activity, and lipogenesis.
  • Investigating the effect of Notch gain-of-function and rapamycin treatment.

Main Results:

  • Liver-specific Notch ablation or inhibition prevented diet-induced or genetic hepatosteatosis by blocking mTORC1 activity.
  • Notch gain-of-function induced fatty liver through constitutive mTORC1 activation, an effect reversed by rapamycin.
  • Notch signaling enhances mTORC1 complex stability, promoting sterol regulatory element binding transcription factor 1c (Srebp1c)-mediated lipogenesis.

Conclusions:

  • Notch signaling is a key driver of hepatic steatosis via mTORC1 activation and subsequent lipogenesis.
  • Targeting Notch signaling can decouple Akt activation from lipid accumulation, offering a novel therapeutic strategy for fatty liver disease.
  • The Notch pathway represents a druggable target for managing metabolic dysfunction in the liver.

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