Hepatic retromer is essential for systemic cholesterol homeostasis by regulating lysosomal cholesterol handling
Year: 2026
Type: article
Abstract: Background Disturbed hepatic cholesterol homeostasis is associated with multiple diseases, including atherosclerotic cardiovascular disease and metabolic dysfunction– associated steatotic liver disease. The endo-lysosomal system is essential for cholesterol uptake and intracellular distribution, yet the mechanisms governing these processes remain incompletely understood. Here, we investigated the impact of hepatic VPS35, a subunit of the endosomal sorting complex retromer, on hepatocellular and whole-body cholesterol homeostasis. Methods We generated a liver-specific Vps35 knockout mouse model ( Vps35 HepKO ) and applied biochemical analyses, proteomics, and stable-isotope-labeled tracers to quantify critical processes of cholesterol metabolism. Human iPSC-derived liver organoids and CRISPR technology were used to translate our findings to humans. Mechanistic studies were performed in precision-cut liver slices from WT and Vps35 HepKO mice. Results Hepatic VPS35 deficiency led to an increase in endo-lysosomal degradative compartments and a marked reduction in specific lysosomal proteins, including lysosomal acid lipase (LAL), Scavenger Receptor Class B Member 2 (SCARB2), and Niemann-Pick type C1 (NPC1). Using pathway-specific inhibitors, we showed that VPS35 loss impairs the translation of SCABR2 and NPC1. Consistently, human iPSC-derived liver organoids lacking VPS35 also exhibited reduced expression of NPC1 and SCARB2 proteins. The decrease in these lysosomal proteins correlated with increased cholesterol levels in the plasma and liver of Vps35 HepKO mice. This was likely explained by the disrupted cholesterol trafficking through the endo-lysosomal system, delayed plasma cholesterol turnover, and upregulated cholesterol biosynthesis. Conclusion These findings uncover a previously unknown role for the hepatic retromer complex in maintaining systemic cholesterol homeostasis. Beyond its established function in endosomal cargo transport, we now demonstrate that retromer is also essential for lysosomal cholesterol handling. This role is mediated by regulating key lysosomal proteins involved in cholesterol metabolism, including LAL, NPC1, and SCARB2.
Source: Molecular Metabolism
Authors: Cristy R.C. Verzijl, Markus G. Barbosa, Dyonne Y. Vos, Andries H. Heida, Amandine Caillaud, Lauri Vanharanta, Xiaoke Ge, Joël J. Tissink, Mirjam H. Koster, Marieke Smit, Nicolette Huijkman, Niels J. Kloosterhuis, Aurore Girardeau, Zoé Begué-Racapé, Vincent W. Bloks, Rick Havinga, Marceline M. Fuh, Fulvio Reggiori, Muriel Mari, Ludger Scheja, Folkert Kuipers, Santiago Solé-Domènech, Sander Kooijman, Joerg Heeren, Jan Freark de Boer, Patrick C.N. Rensen, Elina Ikonen, Antoine Rimbert, Justina C. Wolters, Jan Albert Kuivenhoven, Bart van de Sluis
Institutions: University Medical Center Groningen, University of Groningen, Centre National de la Recherche Scientifique, Inserm, Centre Hospitalier Universitaire de Nantes, Institut du Thorax, Nantes Université, University of Helsinki, Minerva Foundation, Leiden University Medical Center, University Medical Center Hamburg-Eppendorf, Aarhus University, Weill Cornell Medicine
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,270
Funders: Stichting De Cock-Hadders, European Commission, Deutsche Forschungsgemeinschaft, ZonMw, Academy of Finland, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Universitair Medisch Centrum Groningen, Aard- en Levenswetenschappen, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, H2020 Marie Skłodowska-Curie Actions
Awards: G1117131603, Netherlands Electron Microscopy Infrastructure (NEMI), G3267655354, G3375755183, G3377982111, G4012842235, G4473571678, EU Training Network in understanding the molecular regulation and the role of endo-lysosomal processes in cardio-metabolic diseases, G6182688759, Functional Genomics for the identification of novel regulators of hepatic lipid metabolism: harnessing in vivo CRISPR/Cas9-based strategies (GENESIS), G8941364411, G8977186329
OpenAlex ID: W7221436412