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; Giannino Del Sal

doi:10.1038/s41467-019-09152-7

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^*, Giannino Del Sal

^*Corresponding author for this work

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

161 Citations (Scopus)

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.

Original language	English
Article number	1326
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09152-7
Publication status	Published - 1 Dec 2019

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@article{434f3778e3434365a7d7aa76334cab8e,

title = "Sterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism",

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.",

author = "Rebecca Bertolio and Francesco Napoletano and Miguel Mano and Sebastian Maurer-Stroh and Marco Fantuz and Alessandro Zannini and Silvio Bicciato and Giovanni Sorrentino and {Del Sal}, Giannino",

note = "Funding Information: We thank A. Testa for discussions and proofreading the manuscript. We acknowledge G. Pastore for technical support. We acknowledge support by the Italian Health Ministry (RF-2011-02346976 to G.D.S.), the Italian University and Research Ministry (PRIN-2015-8KZKE3), the Cariplo Foundation (grant no. 2014-0812), Beneficentia-Stiftung, the European Regional Development Fund Interreg Italia-{\"O}sterreich (PreCanMed ITAT1009), Fondazione CRTrieste and Regione Autonoma Friuli Venezia Giulia (Contributo ex art. 15 L.R. 17/2014) to G.D.S. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) and AIRC Special Program Molecular Clinical Oncology {\textquoteleft}5 per mille{\textquoteright} (grant no. 10016) to G.D.S. and S.B., and AIRC IG (grant no. 17659) to G.D.S. M.M. was supported by the FCT Investigator Programme IF/00694/2013 from the Portuguese Foundation for Science and Technology (FCT), Portugal. G.S. is a recipient of a FEBS long-term fellowship. R.B. and M.F. are supported by a FIRC-AIRC fellowship for Italy. F.N. was supported by a European Union FP7/ Associazione Italiana per la Ricerca sul Cancro (AIRC) Reintegration Grant (iCARE N° 17885) and a University of Trieste FRA 2018 Starting Grant. We thank the Confocal microscopy facility of the University of Trieste. We also thank F. Feiguin (International Centre for Genetic Engineering and Biotechnology, Trieste, Italy) for providing Drosophila cells and lines, and the Vienna Drosophila Resource Center, the Bloomington Drosophila Stock Center, P. Bellosta (University of Trento, Italy), and B. Mollereau (Ecole Normale Superierure de Lyon, France) for providing Drosophila lines. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

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doi = "10.1038/s41467-019-09152-7",

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T1 - Sterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism

AU - Bertolio, Rebecca

AU - Napoletano, Francesco

AU - Mano, Miguel

AU - Maurer-Stroh, Sebastian

AU - Fantuz, Marco

AU - Zannini, Alessandro

AU - Bicciato, Silvio

AU - Sorrentino, Giovanni

AU - Del Sal, Giannino

N1 - Funding Information: We thank A. Testa for discussions and proofreading the manuscript. We acknowledge G. Pastore for technical support. We acknowledge support by the Italian Health Ministry (RF-2011-02346976 to G.D.S.), the Italian University and Research Ministry (PRIN-2015-8KZKE3), the Cariplo Foundation (grant no. 2014-0812), Beneficentia-Stiftung, the European Regional Development Fund Interreg Italia-Österreich (PreCanMed ITAT1009), Fondazione CRTrieste and Regione Autonoma Friuli Venezia Giulia (Contributo ex art. 15 L.R. 17/2014) to G.D.S. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) and AIRC Special Program Molecular Clinical Oncology ‘5 per mille’ (grant no. 10016) to G.D.S. and S.B., and AIRC IG (grant no. 17659) to G.D.S. M.M. was supported by the FCT Investigator Programme IF/00694/2013 from the Portuguese Foundation for Science and Technology (FCT), Portugal. G.S. is a recipient of a FEBS long-term fellowship. R.B. and M.F. are supported by a FIRC-AIRC fellowship for Italy. F.N. was supported by a European Union FP7/ Associazione Italiana per la Ricerca sul Cancro (AIRC) Reintegration Grant (iCARE N° 17885) and a University of Trieste FRA 2018 Starting Grant. We thank the Confocal microscopy facility of the University of Trieste. We also thank F. Feiguin (International Centre for Genetic Engineering and Biotechnology, Trieste, Italy) for providing Drosophila cells and lines, and the Vienna Drosophila Resource Center, the Bloomington Drosophila Stock Center, P. Bellosta (University of Trento, Italy), and B. Mollereau (Ecole Normale Superierure de Lyon, France) for providing Drosophila lines. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-019-09152-7

M3 - Article

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AN - SCOPUS:85063333014

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1326

ER -

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

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