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Published on: November 8, 2016
mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway
Timothy R Peterson1, Shomit S Sengupta, Thurl E Harris
1Whitehead Institute for Biomedical Research, Koch Center for Integrative Cancer Research at MIT, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Cell
|August 6, 2011
Summary
The nutrient kinase mTOR complex 1 (mTORC1) controls growth by regulating lipin 1 nuclear entry. This mechanism impacts SREBP activity, influencing gene transcription and metabolic disease resistance in mice.
Area of Science:
- Cellular Biology
- Metabolism
- Molecular Biology
Background:
- The mechanistic target of rapamycin complex 1 (mTORC1) is a key regulator of cellular growth and metabolism.
- Sterol regulatory element-binding proteins (SREBPs) are crucial transcription factors for lipid and cholesterol synthesis.
- The precise mechanisms by which mTORC1 influences SREBP activity remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanism linking mTORC1 signaling to SREBP function.
- To investigate the role of lipin 1 in mediating mTORC1-dependent regulation of lipogenesis and sterolgenesis.
- To determine the in vivo relevance of the mTORC1-lipin 1-SREBP pathway in diet-induced metabolic disorders.
Main Methods:
- Utilized biochemical assays to assess protein interactions and enzymatic activity.
- Employed cell-based assays to monitor SREBP target gene expression and promoter activity.
- Conducted in vivo studies using mouse models with liver-specific mTORC1 inhibition and high-fat/cholesterol diets.
Main Results:
- Demonstrated that mTORC1 controls the nuclear translocation of lipin 1, a phosphatidic acid phosphatase.
- Showed that dephosphorylated, nuclear lipin 1 is essential for mediating mTORC1's effects on SREBP activity and target gene expression.
- Found that inhibiting hepatic mTORC1 confers resistance to diet-induced hepatic steatosis and hypercholesterolemia, dependent on lipin 1.
Conclusions:
- Established lipin 1 as a critical mediator in the mTORC1-SREBP signaling axis.
- Identified the nuclear entry of lipin 1 as a key regulatory step controlled by mTORC1.
- Highlighted the therapeutic potential of targeting the mTORC1-lipin 1 pathway for metabolic diseases.
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