title: Wnt directs the endosomal flux of LDL-derived cholesterol and lipid droplet homeostasis.
abstract: The Wnt pathway, which controls crucial steps of the development and differentiation programs, has been proposed to influence lipid storage and homeostasis. In this paper, using an unbiased strategy based on high-content genome-wide RNAi screens that monitored lipid distribution and amounts, we find that Wnt3a regulates cellular cholesterol. We show that Wnt3a stimulates the production of lipid droplets and that this stimulation strictly depends on endocytosed, LDL-derived cholesterol and on functional early and late endosomes. We also show that Wnt signaling itself controls cholesterol endocytosis and flux along the endosomal pathway, which in turn modulates cellular lipid homeostasis. These results underscore the importance of endosome functions for LD formation and reveal a previously unknown regulatory mechanism of the cellular programs controlling lipid storage and endosome transport under the control of Wnt signaling.
authors: Department of Biochemistry, University of Geneva, Geneva, Switzerland.
authors: Cameron C
authors: CC
authors: Scott
authors: Department of Biochemistry, University of Geneva, Geneva, Switzerland.
authors: Stefania
authors: S
authors: Vossio
authors: Department of Biochemistry, University of Geneva, Geneva, Switzerland.
authors: Fabrizio
authors: F
authors: Vacca
authors: Faculty of Sciences, Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
authors: Berend
authors: B
authors: Snijder
authors: Department of Biochemistry, University of Geneva, Geneva, Switzerland.
authors: Jorge
authors: J
authors: Larios
authors: Department of Biochemistry, University of Geneva, Geneva, Switzerland.
authors: Olivier
authors: O
authors: Schaad
authors: Vital-IT Group, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
authors: Nicolas
authors: N
authors: Guex
authors: Vital-IT Group, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
authors: Dmitry
authors: D
authors: Kuznetsov
authors: Vital-IT Group, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
authors: Olivier
authors: O
authors: Martin
authors: Biomolecular Screening Facility, SV-PTECH-PTCB, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
authors: Marc
authors: M
authors: Chambon
authors: Biomolecular Screening Facility, SV-PTECH-PTCB, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
authors: Gerardo
authors: G
authors: Turcatti
authors: Faculty of Sciences, Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
authors: Lucas
authors: L
authors: Pelkmans
authors: Department of Biochemistry, University of Geneva, Geneva, Switzerland jean.gruenberg@unige.ch.
authors: Jean
authors: J
authors: Gruenberg
mesh_terms: D000818:Animals; D002460:Cell Line; D008078:Cholesterol, LDL / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D004847:Epithelial Cells / Q000648:ultrastructure; D020869:Gene Expression Profiling; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006706:Homeostasis; D006801:Humans; D007739:L Cells; D066292:Lipid Droplets / Q000378:metabolism*; D051379:Mice; D019301:Oleic Acid / Q000494:pharmacology; D034622:RNA Interference; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism
chemical_list: D008078:Cholesterol, LDL; C555510:WNT3A protein, human; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D019301:Oleic Acid
keywords: LDL‐derived cholesterol; canonical Wnt signaling; endosomes; functional genomics; lipid droplets