mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway

SummaryThe 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 To listen to this audio, enable JavaScript on your browser. However, you can download and play the audio by clicking on the icon belowHelp with MP3 filesOptionsDownload audio (3120 K)

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (159 K)Download as PowerPoint slideHighlights► Nuclear eccentricity is a nutrient- and mTORC1-regulated cellular phenotype ► Lipin 1 is a rapamycin-resistant mTORC1 substrate ► mTORC1-regulated lipin 1 nuclear translocation controls SREBP transcriptional activity ► mTORC1/lipin 1 controls diet-induced hepatic steatosis and hypercholesterolemia