mTORC1 controls lipin-1 nuclear localization to regulate SREBP and lipid synthesis.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mammalian cells |
| Journal | Cell |
| Year | 2011 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.cell.2011.06.034 · PMID 21816276 · Free full text (PMC3336367) |
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.
| Intervention | Genetic/pharmacologic (mTORC1/lipin1) |
| Target | mTORC1 / lipin1 / SREBP |
| Model | Mammalian cells |
| Effect | mTORC1 controls lipin1 nuclear entry to regulate the SREBP lipogenic transcription program |