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Patched regulates lipid homeostasis by controlling cellular cholesterol levels

Author

Listed:
  • Carla E. Cadena del Castillo

    (Biozentrum, University of Basel)

  • J. Thomas Hannich

    (University of Geneva
    CeMM - Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Andres Kaech

    (University of Zurich)

  • Hirohisa Chiyoda

    (Graduate School of Pharmaceutical Sciences, University of Tokyo)

  • Jonathan Brewer

    (Villum Center for Bioanalytical Sciences, University of Southern Denmark)

  • Masamitsu Fukuyama

    (Graduate School of Pharmaceutical Sciences, University of Tokyo)

  • Nils J. Færgeman

    (Villum Center for Bioanalytical Sciences, University of Southern Denmark)

  • Howard Riezman

    (University of Geneva)

  • Anne Spang

    (Biozentrum, University of Basel)

Abstract

Hedgehog (Hh) signaling is essential during development and in organ physiology. In the canonical pathway, Hh binding to Patched (PTCH) relieves the inhibition of Smoothened (SMO). Yet, PTCH may also perform SMO-independent functions. While the PTCH homolog PTC-3 is essential in C. elegans, worms lack SMO, providing an excellent model to probe non-canonical PTCH function. Here, we show that PTC-3 is a cholesterol transporter. ptc-3(RNAi) leads to accumulation of intracellular cholesterol and defects in ER structure and lipid droplet formation. These phenotypes were accompanied by a reduction in acyl chain (FA) length and desaturation. ptc-3(RNAi)-induced lethality, fat content and ER morphology defects were rescued by reducing dietary cholesterol. We provide evidence that cholesterol accumulation modulates the function of nuclear hormone receptors such as of the PPARα homolog NHR-49 and NHR-181, and affects FA composition. Our data uncover a role for PTCH in organelle structure maintenance and fat metabolism.

Suggested Citation

  • Carla E. Cadena del Castillo & J. Thomas Hannich & Andres Kaech & Hirohisa Chiyoda & Jonathan Brewer & Masamitsu Fukuyama & Nils J. Færgeman & Howard Riezman & Anne Spang, 2021. "Patched regulates lipid homeostasis by controlling cellular cholesterol levels," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24995-9
    DOI: 10.1038/s41467-021-24995-9
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