mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway.

By Timothy R. Peterson, Shomit Sengupta, T. Harris, Anne E Carmack, S. A. Kang, E. Balderas, D. Guertin, Katherine L. Madden, Anne E Carpenter, B. Finck and 1 more. Cell, 2011

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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.

Subfields: Biochemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3f3586a493e2155578356d7d2c53845d77dea1f6

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Citations in the corpus

mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “…to low sterol levels, mTORC1 signaling can also activate SREBP independently through both an S6K1-dependent mechanism (Düvel et al., 2010) as well as through the phosphorylation of an additional substrate, Lipin1, which inhibits SREBP in the absence of mTORC1 signaling (Peterson et al., 2011).”
Energy Metabolism in the Liver (2014, positive): “Raptor, prevents dietary hepatic steatosis (207).”
Cellular Fatty Acid Metabolism and Cancer (2013, background): “On the other hand, etomoxir, an inhibitor of CPT1, and ranolazine, an indirect inhibitor of FA oxidation, may kill cancer cells (Samudio et al., 2010; Pike et al., 2011).”
The Neurology of mTOR (2014, positive): “Among the best-studied transcription factors regulated by mTORC1 are the sterol-response binding proteins (SREBPs), which regulate lipogenesis (Peterson et al., 2011).”
Cancer Cell Metabolism: One Hallmark, Many Faces (2012, background): “Recent studies have shown that SREBP-1 is also a downstream effector of mTORC1 (59, 60), thereby affording mTORC1 with an additional mode for regulating cell growth.”
ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs (2014, background): “SREBF1 expression increases with age in rat brains (Okamoto et al. 2006), SREBF1-mediated lipogenesis is involved in senescence (Kim et al. 2010), SREBF2 regulates autophagy (Seo et al. 2011), and SREBF activity is regulated by mTOR complex 1 (Peterson et al. 2011).”
A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB (2012, background): “Recent ﬁndings suggest that mTORC1 phosphorylates its target proteins at multiple sites (Hsu et al , 2011; Peterson et al , 2011; Yu et al , 2011).”
MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATIONS (2012, background): “New and hemizygous mutations were found in CTDNEP1 (previously known as DULLARD ), a phosphatase with roles in Xenopus neural development through regulation of BMP receptors 16 , and as a direct regulator of LIPIN, an integral component of the mTOR complex 17 .”
Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease (2023, background): “73 Overall, the regulation of SREBP by mTORC1 provides an important mechanism by which mTORC1 can promote lipid synthesis and support cellular growth and proliferation (Figs.”
The PI3K/AKT pathway in obesity and type 2 diabetes (2018, background): “In the feeding state, SREBP-1c is regulated by four pathways: activated AKT stimulates liver X receptor (LXR), which is require for SREBP-1c transcription [64]; activated AKT stimulates mTORC1 to activate SREBP-1c transcription, and mTORC1 also inhibits Lipin-1, which decreases the half-life of nucl”
Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy and mitochondrial fusion dynamics (2015, background): “For example, the major autophagy regulator mammalian target of rapamycin (mTOR) is rapidly inactivated during HBSS starvation but not during serum starvation alone (Peterson et al., 2011).”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “additional substrate, Lipin1, which inhibits SREBP in the absence of mTORC1 signaling (Peterson et al., 2011).”