Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways

Cell Metab. 2011 Jul 6;14(1):21-32. doi: 10.1016/j.cmet.2011.06.002.

Abstract

Through unknown mechanisms, insulin activates the sterol regulatory element-binding protein (SREBP1c) transcription factor to promote hepatic lipogenesis. We find that this induction is dependent on the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). To further define the role of mTORC1 in the regulation of SREBP1c in the liver, we generated mice with liver-specific deletion of TSC1 (LTsc1KO), which results in insulin-independent activation of mTORC1. Surprisingly, the LTsc1KO mice are protected from age- and diet-induced hepatic steatosis and display hepatocyte-intrinsic defects in SREBP1c activation and de novo lipogenesis. These phenotypes result from attenuation of Akt signaling driven by mTORC1-dependent insulin resistance. Therefore, mTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Hepatocytes / metabolism*
  • Insulin / metabolism
  • Lipogenesis
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes
  • Proteins / metabolism*
  • Proteins / physiology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 1 / antagonists & inhibitors
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Insig2 protein, mouse
  • Insulin
  • Membrane Proteins
  • Multiprotein Complexes
  • Proteins
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt