RT Journal Article
SR Electronic
T1 Patched regulates lipid homeostasis by controlling cellular cholesterol levels
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 816256
DO 10.1101/816256
A1 Carla E. Cadena del Castillo
A1 J. Thomas Hannich
A1 Andres Kaech
A1 Hirohisa Chiyoda
A1 Masamitsu Fukuyama
A1 Nils J. Færgeman
A1 Howard Riezman
A1 Anne Spang
YR 2019
UL http://biorxiv.org/content/early/2019/10/23/816256.abstract
AB 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 storage 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 novel role for PTCH in organelle structure maintenance and fat metabolism.