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.

Drug‐induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann–Pick type C cells and mice

“…Figure 1B shows an example of a 384-well plate stained for cholesterol (green) and LBPA (red) with four micrographs stitched together per well. The broad dynamic range of the detection system and its robustness, as already revealed in our previous RNAi screens with the same detection system [14], are illustrated by the staining with both markers in U18666A-treated versus control cells (Fig 1C and D). The broad dynamic range of the detection system and its robustness, as already revealed in our previous RNAi screens with the same detection system [14], are illustrated by the staining with both markers in U18666A-treated versus control cells (Fig 1C and D).…”

“…In addition to this uncommon distribution, LBPA also exhibits an unusual stereoconfiguration [9,10], and its metabolism is poorly understood [11,12]. Interfering with LBPA functions causes cholesterol accumulation in late endosomes, phenocopying NPC [6,13], and inhibits Wnt-induced biogenesis of lipid droplets [14]. In fact, our data indicate that LBPA plays a direct role in regulating the cholesterol flux through endosomes.…”

“…This enlargement of the endosomal system presumably reflects the attempt to compensate for the accumulation of storage materials. Given its role in endosomal cholesterol transport [6,14,28], we propose that LBPA then becomes limiting, because its capacity to accommodate-or buffer-excess cholesterol in NPC endosomes is overwhelmed. Given its role in endosomal cholesterol transport [6,14,28], we propose that LBPA then becomes limiting, because its capacity to accommodate-or buffer-excess cholesterol in NPC endosomes is overwhelmed.…”

“…Concomitant with this increase in endosomal volume, protein and lipid [21], total LBPA levels are also increased [6]. Given the role of LBPA in endosomal cholesterol transport [6,14,28], we reasoned that the capacity of LBPA to accommodateor buffer-excess cholesterol may eventually become limiting in NPC endosomes. Given the role of LBPA in endosomal cholesterol transport [6,14,28], we reasoned that the capacity of LBPA to accommodateor buffer-excess cholesterol may eventually become limiting in NPC endosomes.…”

Expression of the Frizzled receptors and their co-receptors in calcified human aortic valves

“…Both diseases share common risk factors and are initiated by lipid deposition and inflammation, triggered by endothelial damage. The upregulation of Wnt/LRP5 signaling pathway is considered to be a trigger for calcification (Caira et al 2006;Rajamannan 2011a (Scott et al 2015). Thus, the upregulation of LRP5/6 in calcified aortic valves in our present study is indicative of the involvement of the Wnt signaling pathway and the Frizzled LRP5/6 co-receptors in the pathogenesis of AVC and atherosclerosis.…”