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 transcr...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Elsevier
2014
|
| Online Access: | http://hdl.handle.net/1721.1/92259 https://orcid.org/0000-0002-1446-7256 |
| _version_ | 1826202082602909696 |
|---|---|
| author | Peterson, Timothy R. Sengupta, Shomit S. Harris, Thurl E. Carpenter, Anne E. Kang, Seong A. Balderas, Eric Guertin, David A. Madden, Katherine L. Finck, Brian N. Sabatini, David M. Kang, Seong A. Peterson, Timothy Richard Sengupta, Shomit Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Peterson, Timothy R. Sengupta, Shomit S. Harris, Thurl E. Carpenter, Anne E. Kang, Seong A. Balderas, Eric Guertin, David A. Madden, Katherine L. Finck, Brian N. Sabatini, David M. Kang, Seong A. Peterson, Timothy Richard Sengupta, Shomit Sabatini, David |
| author_sort | Peterson, Timothy R. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T12:01:36Z |
| format | Article |
| id | mit-1721.1/92259 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:01:36Z |
| publishDate | 2014 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/922592022-10-01T07:41:09Z mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway Peterson, Timothy R. Sengupta, Shomit S. Harris, Thurl E. Carpenter, Anne E. Kang, Seong A. Balderas, Eric Guertin, David A. Madden, Katherine L. Finck, Brian N. Sabatini, David M. Kang, Seong A. Peterson, Timothy Richard Sengupta, Shomit Sabatini, David Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Peterson, Timothy R. Sengupta, Shomit S. Kang, Seong A. Balderas, Eric Sabatini, David M. 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. National Institutes of Health (U.S.) (Grant R01 AI47389) National Institutes of Health (U.S.) (Grant R01 CA103866) LAM Foundation (Award) W. M. Keck Foundation (Award) American Diabetes Association (Fellowship) Virginia and D.K. Ludwig Fund for Cancer Research (Fellowship) Jane Coffin Childs Memorial Fund (Fellowship) 2014-12-10T19:02:19Z 2014-12-10T19:02:19Z 2011-08 2011-05 Article http://purl.org/eprint/type/JournalArticle 00928674 1097-4172 http://hdl.handle.net/1721.1/92259 Peterson, Timothy R., Shomit S. Sengupta, Thurl E. Harris, Anne E. Carmack, Seong A. Kang, Eric Balderas, David A. Guertin, et al. “mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway.” Cell 146, no. 3 (August 2011): 408–420. © 2011 Elsevier Inc. https://orcid.org/0000-0002-1446-7256 en_US http://dx.doi.org/10.1016/j.cell.2011.06.034 Cell Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier |
| spellingShingle | Peterson, Timothy R. Sengupta, Shomit S. Harris, Thurl E. Carpenter, Anne E. Kang, Seong A. Balderas, Eric Guertin, David A. Madden, Katherine L. Finck, Brian N. Sabatini, David M. Kang, Seong A. Peterson, Timothy Richard Sengupta, Shomit Sabatini, David mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway |
| title | mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway |
| title_full | mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway |
| title_fullStr | mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway |
| title_full_unstemmed | mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway |
| title_short | mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway |
| title_sort | mtor complex 1 regulates lipin 1 localization to control the srebp pathway |
| url | http://hdl.handle.net/1721.1/92259 https://orcid.org/0000-0002-1446-7256 |
| work_keys_str_mv | AT petersontimothyr mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway AT senguptashomits mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway AT harristhurle mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway AT carpenterannee mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway AT kangseonga mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway AT balderaseric mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway AT guertindavida mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway AT maddenkatherinel mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway AT finckbriann mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway AT sabatinidavidm mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway AT kangseonga mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway AT petersontimothyrichard mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway AT senguptashomit mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway AT sabatinidavid mtorcomplex1regulateslipin1localizationtocontrolthesrebppathway |