Extracellular matrix (ECM) mechanical cues have powerful effects on cell proliferation, differentiation and death. Here, starting from an unbiased metabolomics approach, we identify synthesis of neutral lipids as a general response to mechanical signals delivered by cell–matrix adhesions. Extracellular physical cues reverberate on the mechanical properties of the Golgi apparatus and regulate the Lipin-1 phosphatidate phosphatase. Conditions of reduced actomyosin contractility lead to inhibition of Lipin-1, accumulation of SCAP/SREBP to the Golgi apparatus and activation of SREBP transcription factors, in turn driving lipid synthesis and accumulation. This occurs independently of YAP/TAZ, mTOR and AMPK, and in parallel to feedback control by sterols. Regulation of SREBP can be observed in a stiffened diseased tissue, and contributes to the pro-survival activity of ROCK inhibitors in pluripotent stem cells. We thus identify a general mechanism centered on Lipin-1 and SREBP that links the physical cell microenvironment to a key metabolic pathway.
|Titolo:||Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP|
|Parole Chiave:||Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell-Matrix Junctions; Cellular Microenvironment; Cues; Extracellular Matrix; Golgi Apparatus; Humans; Metabolomics; Phosphatidate Phosphatase; Signal Transduction; Sterol Regulatory Element Binding Proteins; Lipid Metabolism|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
|Data di pubblicazione:||mar-2019|
|Digital Object Identifier (DOI):||10.1038/s41556-018-0270-5|
|Appare nelle tipologie:||01 - Articolo su periodico|