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mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway.

The nutrient- and growth factor-responsive kinase mTOR complex 1 (mTORC1) regulates many processes that control growth, including protein synthesis, autophagy, and lipogenesis. Through unknown mechanisms, mTORC1 promotes the function of SREBP, a master regulator of lipo- and sterolgenic gene transcription. Here, we demonstrate that mTORC1 regulates SREBP by controlling the nuclear entry of lipin 1, a phosphatidic acid phosphatase. Dephosphorylated, nuclear, catalytically active lipin 1 promotes nuclear remodeling and mediates the effects of mTORC1 on SREBP target gene, SREBP promoter activity, and nuclear SREBP protein abundance. Inhibition of mTORC1 in the liver significantly impairs SREBP function and makes mice resistant, in a lipin 1-dependent fashion, to the hepatic steatosis and hypercholesterolemia induced by a high-fat and -cholesterol diet. These findings establish lipin 1 as a key component of the mTORC1-SREBP pathway.

Pubmed ID: 21816276

Authors

  • Peterson TR
  • Sengupta SS
  • Harris TE
  • Carmack AE
  • Kang SA
  • Balderas E
  • Guertin DA
  • Madden KL
  • Carpenter AE
  • Finck BN
  • Sabatini DM

Journal

Cell

Publication Data

August 5, 2011

Associated Grants

  • Agency: NIAID NIH HHS, Id: R01 AI47389
  • Agency: NCI NIH HHS, Id: R01 CA103866
  • Agency: NCI NIH HHS, Id: R01 CA103866
  • Agency: NCI NIH HHS, Id: R01 CA103866-08
  • Agency: NCI NIH HHS, Id: R01 CA103866-09
  • Agency: NCI NIH HHS, Id: R01 CA129105
  • Agency: NCI NIH HHS, Id: R01 CA129105-04
  • Agency: NCI NIH HHS, Id: R01 CA129105-05
  • Agency: NIDDK NIH HHS, Id: R01 DK078187
  • Agency: NIGMS NIH HHS, Id: R01 GM089652
  • Agency: NIGMS NIH HHS, Id: R01 GM089652-01
  • Agency: NIAID NIH HHS, Id: R37 AI047389
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Humans
  • Lipid Metabolism
  • Male
  • Mice
  • Multiprotein Complexes
  • Nuclear Proteins
  • Phosphatidate Phosphatase
  • Proteins
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • TOR Serine-Threonine Kinases