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Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans

Author

Listed:
  • Sebastian Hendrix

    (University of Amsterdam)

  • Jenina Kingma

    (University of Amsterdam)

  • Roelof Ottenhoff

    (University of Amsterdam)

  • Masoud Valiloo

    (University of Amsterdam)

  • Monika Svecla

    (Università degli Studi di Milano)

  • Lobke F. Zijlstra

    (University of Amsterdam)

  • Vinay Sachdev

    (University of Amsterdam)

  • Kristina Kovac

    (University of Amsterdam)

  • Johannes H. M. Levels

    (University of Amsterdam)

  • Aldo Jongejan

    (University of Amsterdam)

  • Jan F. Boer

    (University of Groningen
    University of Groningen)

  • Folkert Kuipers

    (University of Groningen
    University of Groningen)

  • Antoine Rimbert

    (CNRS, INSERM)

  • Giuseppe D. Norata

    (Università degli Studi di Milano)

  • Anke Loregger

    (University of Amsterdam
    Myllia Biotechnology GmbH)

  • Noam Zelcer

    (University of Amsterdam)

Abstract

The sterol regulatory element binding proteins (SREBPs) are transcription factors that govern cholesterol and fatty acid metabolism. We recently identified SPRING as a post-transcriptional regulator of SREBP activation. Constitutive or inducible global ablation of Spring in mice is not tolerated, and we therefore develop liver-specific Spring knockout mice (LKO). Transcriptomics and proteomics analysis reveal attenuated SREBP signaling in livers and hepatocytes of LKO mice. Total plasma cholesterol is reduced in male and female LKO mice in both the low-density lipoprotein and high-density lipoprotein fractions, while triglycerides are unaffected. Loss of Spring decreases hepatic cholesterol and triglyceride content due to diminished biosynthesis, which coincides with reduced very-low-density lipoprotein secretion. Accordingly, LKO mice are protected from fructose diet-induced hepatosteatosis. In humans, we find common genetic SPRING variants that associate with circulating high-density lipoprotein cholesterol and ApoA1 levels. This study positions SPRING as a core component of hepatic SREBP signaling and systemic lipid metabolism in mice and humans.

Suggested Citation

  • Sebastian Hendrix & Jenina Kingma & Roelof Ottenhoff & Masoud Valiloo & Monika Svecla & Lobke F. Zijlstra & Vinay Sachdev & Kristina Kovac & Johannes H. M. Levels & Aldo Jongejan & Jan F. Boer & Folke, 2023. "Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40943-1
    DOI: 10.1038/s41467-023-40943-1
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    References listed on IDEAS

    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    3. Anke Loregger & Matthijs Raaben & Joppe Nieuwenhuis & Josephine M. E. Tan & Lucas T. Jae & Lisa G. Hengel & Sebastian Hendrix & Marlene Berg & Saskia Scheij & Ji-Ying Song & Ivo J. Huijbers & Lona J. , 2020. "Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    4. Sarah E. Graham & Shoa L. Clarke & Kuan-Han H. Wu & Stavroula Kanoni & Greg J. M. Zajac & Shweta Ramdas & Ida Surakka & Ioanna Ntalla & Sailaja Vedantam & Thomas W. Winkler & Adam E. Locke & Eirini Ma, 2021. "The power of genetic diversity in genome-wide association studies of lipids," Nature, Nature, vol. 600(7890), pages 675-679, December.
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