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

Rebecca Bertolio, Francesco Napoletano, Miguel Mano, Sebastian Maurer-Stroh, Marco Fantuz, Alessandro Zannini, Silvio Bicciato, Giovanni Sorrentino () and Giannino Del Sal ()
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Rebecca Bertolio: Laboratorio Nazionale CIB
Francesco Napoletano: Laboratorio Nazionale CIB
Miguel Mano: University of Coimbra
Sebastian Maurer-Stroh: Agency for Science Technology and Research (A*STAR)
Marco Fantuz: Laboratorio Nazionale CIB
Alessandro Zannini: Laboratorio Nazionale CIB
Silvio Bicciato: University of Modena and Reggio Emilia
Giovanni Sorrentino: Laboratorio Nazionale CIB
Giannino Del Sal: Laboratorio Nazionale CIB

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09152-7

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