title: mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway.
abstract: 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.
authors.affiliation: Whitehead Institute for Biomedical Research, Koch Center for Integrative Cancer Research at MIT, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Peterson
authors.forename: Shomit S
authors.initials: SS
authors.lastname: Sengupta
authors.forename: Thurl E
authors.initials: TE
authors.lastname: Harris
authors.forename: Anne E
authors.initials: AE
authors.lastname: Carmack
authors.forename: Seong A
authors.initials: SA
authors.lastname: Kang
authors.forename: Eric
authors.initials: E
authors.lastname: Balderas
authors.forename: David A
authors.initials: DA
authors.lastname: Guertin
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Madden
authors.forename: Anne E
authors.initials: AE
authors.lastname: Carpenter
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
mesh_terms: D000818:Animals; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009687:Nuclear Proteins / Q000378:metabolism*; D010711:Phosphatidate Phosphatase; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
chemical_list: D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D011506:Proteins; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase