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Sterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism

Author

Listed:
  • Rebecca Bertolio

    (Laboratorio Nazionale CIB
    Università degli Studi di Trieste)

  • Francesco Napoletano

    (Laboratorio Nazionale CIB
    Università degli Studi di Trieste)

  • Miguel Mano

    (University of Coimbra)

  • Sebastian Maurer-Stroh

    (Agency for Science Technology and Research (A*STAR)
    National University of Singapore (NUS))

  • Marco Fantuz

    (Laboratorio Nazionale CIB
    International School for Advanced Studies (SISSA))

  • Alessandro Zannini

    (Laboratorio Nazionale CIB
    Università degli Studi di Trieste)

  • Silvio Bicciato

    (University of Modena and Reggio Emilia)

  • Giovanni Sorrentino

    (Laboratorio Nazionale CIB
    Ecole Polytechnique Fédérale de Lausanne)

  • Giannino Del Sal

    (Laboratorio Nazionale CIB
    Università degli Studi di Trieste
    the FIRC Institute of Molecular Oncology)

Abstract

Sterol regulatory element binding proteins (SREBPs) are a family of transcription factors that regulate lipid biosynthesis and adipogenesis by controlling the expression of several enzymes required for cholesterol, fatty acid, triacylglycerol and phospholipid synthesis. In vertebrates, SREBP activation is mainly controlled by a complex and well-characterized feedback mechanism mediated by cholesterol, a crucial bio-product of the SREBP-activated mevalonate pathway. In this work, we identified acto-myosin contractility and mechanical forces imposed by the extracellular matrix (ECM) as SREBP1 regulators. SREBP1 control by mechanical cues depends on geranylgeranyl pyrophosphate, another key bio-product of the mevalonate pathway, and impacts on stem cell fate in mouse and on fat storage in Drosophila. Mechanistically, we show that activation of AMP-activated protein kinase (AMPK) by ECM stiffening and geranylgeranylated RhoA-dependent acto-myosin contraction inhibits SREBP1 activation. Our results unveil an unpredicted and evolutionary conserved role of SREBP1 in rewiring cell metabolism in response to mechanical cues.

Suggested Citation

  • Rebecca Bertolio & Francesco Napoletano & Miguel Mano & Sebastian Maurer-Stroh & Marco Fantuz & Alessandro Zannini & Silvio Bicciato & Giovanni Sorrentino & Giannino Del Sal, 2019. "Sterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09152-7
    DOI: 10.1038/s41467-019-09152-7
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    Cited by:

    1. Rakesh Ganji & Joao A. Paulo & Yuecheng Xi & Ian Kline & Jiang Zhu & Christoph S. Clemen & Conrad C. Weihl & John G. Purdy & Steve P. Gygi & Malavika Raman, 2023. "The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Zhiren Wang & Wenpan Li & Yanhao Jiang & Jonghan Park & Karina Marie Gonzalez & Xiangmeng Wu & Qing-Yu Zhang & Jianqin Lu, 2024. "Cholesterol-modified sphingomyelin chimeric lipid bilayer for improved therapeutic delivery," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Tiago C. Silva & Juan I. Young & Lanyu Zhang & Lissette Gomez & Michael A. Schmidt & Achintya Varma & X. Steven Chen & Eden R. Martin & Lily Wang, 2022. "Cross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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