TY - JOUR
T1 - MTOR complex 1 regulates lipin 1 localization to control the srebp pathway
AU - Peterson, Timothy R.
AU - Sengupta, Shomit S.
AU - Harris, Thurl E.
AU - Carmack, Anne E.
AU - Kang, Seong A.
AU - Balderas, Eric
AU - Guertin, David A.
AU - Madden, Katherine L.
AU - Carpenter, Anne E.
AU - Finck, Brian N.
AU - Sabatini, David M.
N1 - Funding Information:
We thank the following for technical assistance: We thank members of the Sabatini lab (in particular, Mathieu Laplante and Peggy Hsu), Ayce Yesilatay, and Monty Krieger for helpful discussions. D.M.S. is an investigator of the Howard Hughes Medical Institute. This work was additionally supported by grants from the National Institutes of Health (R01 AI47389 and R01 CA103866) to D.M.S.; awards from the Keck Foundation and LAM Foundation to D.M.S.; an NIH R01 GM089652-01 to A.E.C.; fellowships from the American Diabetes Association, Ludwig Cancer Fund, and Jane Coffin Childs Memorial Fund to T.R.P; and an RO1 DK078187 to B.N.F.
PY - 2011/8/5
Y1 - 2011/8/5
N2 - 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. PaperClip:
AB - 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. PaperClip:
UR - http://www.scopus.com/inward/record.url?scp=79961165137&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2011.06.034
DO - 10.1016/j.cell.2011.06.034
M3 - Article
C2 - 21816276
AN - SCOPUS:79961165137
VL - 146
SP - 408
EP - 420
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -