Patched regulates lipid homeostasis by controlling cellular cholesterol levels

Carla E. Cadena del Castillo, J. Thomas Hannich, Andres Kaech, Hirohisa Chiyoda, Jonathan Brewer, Masamitsu Fukuyama, Nils J. Færgeman, Howard Riezman and Anne Spang ()
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Carla E. Cadena del Castillo: Biozentrum, University of Basel
J. Thomas Hannich: University of Geneva
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

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24995-9

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