Patched regulates lipid homeostasis by controlling cellular cholesterol levels

Carla E Cadena Del Castillo,Howard Riezman,Andres Kaech,Masamitsu Fukuyama,Jonathan Brewer,J Thomas Hannich,Anne Spang,Hirohisa Chiyoda,Nils J Færgeman

doi:10.1038/s41467-021-24995-9

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.

Highlights

Hedgehog (Hh) signaling is essential during development and in organ physiology
Our data demonstrate that PTCH controls intracellular cholesterol levels in C. elegans, we show that PTCH thereby impinges on FA metabolism, organellar structure, and fat storage capacity
In order to understand the function of PTCH proteins in C. elegans, we decided first to revisit the phenotypes caused by the depletion of the somatically expressed PTC-3

Summary

Introduction

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). While the PTCH homolog PTC-3 is essential in C. elegans, worms lack SMO, providing an excellent model to probe noncanonical PTCH function. The structures suggest that Hh inhibits PTCH transporter function and plasma membrane cholesterol levels could increase. Such an increase of cholesterol might be sensed through the sterol sensing domain in SMO and thereby activate the GPCR. C. elegans provides an excellent model to study non-canonical, SMO-independent Hh signaling pathways, in particular in somatic tissues. The endoplasmic reticulum (ER) lost most of its reticulate tubular form and developed elaborate sheet structures in the intestine This effect in turn strongly impaired lipid droplet biogenesis, resulting in the inability of the animal to store fat. In addition to the previously reported phenotypes, we noticed that the ptc-3

Methods

Results

Conclusion