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.

Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP / Romani, Patrizia; Brian, Irene; Santinon, Giulia; Pocaterra, Arianna; Audano, Matteo; Pedretti, Silvia; Mathieu, Samuel; Forcato, Mattia; Bicciato, Silvio; Manneville, Jean-Baptiste; Mitro, Nico; Dupont, Sirio. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - 21:3(2019), pp. 338-347.

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