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

Nat Med. 2013 Aug;19(8):1054-60. doi: 10.1038/nm.3259. Epub 2013 Jul 7.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Body Weight / drug effects
  • Cell Line, Tumor
  • Diet, High-Fat
  • Enzyme Activation / drug effects
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Gene Expression Regulation / drug effects
  • HEK293 Cells
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
  • Insulin / pharmacology
  • Insulin Resistance
  • Lipid Metabolism* / drug effects
  • Lipid Metabolism* / genetics
  • Lipogenesis / drug effects
  • Lipogenesis / genetics
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Multiprotein Complexes / metabolism*
  • Protein Stability / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptors, Notch / antagonists & inhibitors*
  • Receptors, Notch / metabolism
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism*
  • Triglycerides / metabolism

Substances

  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Insulin
  • Multiprotein Complexes
  • Rbpj protein, mouse
  • Receptors, Notch
  • Triglycerides
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases