Hepatic retromer is essential for systemic cholesterol homeostasis by regulating lysosomal cholesterol handling
11 affiliations
- 1Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- 2Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, F-44000, France
- 3Department of Anatomy and Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, Finland
- 4Minerva Foundation Institute for Medical Research, Helsinki, Finland
- 5Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands
- 6Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands
- 7Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- 8Department of Biomedicine, Aarhus University, Aarhus, Denmark
- 9European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- 10Department of Biochemistry and Biophysics, Weill Cornell Medicine, New York, USA
- 11Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Abstract
Disturbed hepatic cholesterol homeostasis is associated with atherosclerotic cardiovascular disease (ASCVD) and metabolic dysfunction–associated steatotic liver disease (MASLD). The endo-lysosomal system plays a central role in cholesterol uptake and intracellular trafficking, yet the molecular mechanisms governing these processes remain poorly understood. Here, we identify hepatic vacuolar protein sorting 35 (VPS35), a core component of the retromer complex, as a critical regulator of hepatocellular and systemic cholesterol homeostasis. Liver-specific VPS35 ablation in mice elevated plasma and hepatic cholesterol levels due to impaired hepatic uptake of atherogenic lipoproteins, defective cholesterol trafficking through the endo-lysosomal system, and increased de novo cholesterol biosynthesis. The decreased hepatic uptake of atherogenic lipoproteins was associated with altered subcellular distribution of the low-density lipoprotein receptor (LDLR) and reduced levels of LDLR-related protein 1 (LRP1). The increased hepatic cholesterol content was associated with altered lysosomal ultrastructure and pH and decreased levels of a wide range of lysosomal proteins, including key proteins for lysosomal cholesterol egress, such as lysosomal acid lipase (LAL), scavenger receptor class B member 2 (SCARB2), Niemann–Pick type C1 (NPC1), and NPC2. Collectively, these findings reveal a previously unrecognized function of the hepatic retromer complex in systemic cholesterol homeostasis. Beyond its established role in endosomal cargo transport, VPS35 is essential for lysosomal cholesterol handling by preserving key proteins involved in lysosomal cholesterol metabolism.
Related
- Lysosomal acid lipase regulates cholesterol metabolism during phagosomal maturation
- Perinatal Bisphenol S Exposure Induces Hepatotoxicity in Female Rat Offspring: Insights into Disrupted Hepatic Cholesterol Homeostasis.
- Cholesterol-Mediated Modulation of Collecting Lymphatic Vessel Contractility: Exploring Cholesterol Depletion as a Therapeutic Alternative to Improve Lymphatic Function in Hypercholesterolemia
- Remnant cholesterol and cardiovascular risk in maintenance haemodialysis
- Pharmacological Fingerprinting of Cholesterol Biosynthesis Defects
BibTeX
@article{verzijl2026hepatic,
title = {{Hepatic retromer is essential for systemic cholesterol homeostasis by regulating lysosomal cholesterol handling}},
author = {Cristy R.C. Verzijl and Markus G. Barbosa and Dyonne Y. Vos and Andries H. Heida and Amandine Caillaud and Lauri Vanharanta and Xiaoke Ge and Joël J. Tissink and Mirjam H. Koster and Marieke Smit and Nicolette Huijkman and Niels J. Kloosterhuis and Aurore Girardeau and Zoé Begué-Racapé and Vincent W. Bloks and Rick Havinga and Marceline M. Fuh and Fulvio Reggiori and Muriel Mari and Ludger Scheja and Folkert Kuipers and Santiago Solé-Domènech and Sander Kooijman and Joerg Heeren and Jan Freark de Boer and Patrick C.N. Rensen and Elina Ikonen and Antoine Rimbert and Justina C. Wolters and Jan Albert Kuivenhoven and Bart van de Sluis},
journal = {Molecular Metabolism},
year = {2026},
month = oct,
doi = {10.1016/j.molmet.2026.102456},
url = {https://doi.org/10.1016/j.molmet.2026.102456},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Hepatic retromer is essential for systemic cholesterol homeostasis by regulating lysosomal cholesterol handling
AU - Cristy R.C. Verzijl
AU - Markus G. Barbosa
AU - Dyonne Y. Vos
AU - Andries H. Heida
AU - Amandine Caillaud
AU - Lauri Vanharanta
AU - Xiaoke Ge
AU - Joël J. Tissink
AU - Mirjam H. Koster
AU - Marieke Smit
AU - Nicolette Huijkman
AU - Niels J. Kloosterhuis
AU - Aurore Girardeau
AU - Zoé Begué-Racapé
AU - Vincent W. Bloks
AU - Rick Havinga
AU - Marceline M. Fuh
AU - Fulvio Reggiori
AU - Muriel Mari
AU - Ludger Scheja
AU - Folkert Kuipers
AU - Santiago Solé-Domènech
AU - Sander Kooijman
AU - Joerg Heeren
AU - Jan Freark de Boer
AU - Patrick C.N. Rensen
AU - Elina Ikonen
AU - Antoine Rimbert
AU - Justina C. Wolters
AU - Jan Albert Kuivenhoven
AU - Bart van de Sluis
PY - 2026
DA - 2026/10/11
JO - Molecular Metabolism
DO - 10.1016/j.molmet.2026.102456
UR - https://doi.org/10.1016/j.molmet.2026.102456
AB - Disturbed hepatic cholesterol homeostasis is associated with atherosclerotic cardiovascular disease (ASCVD) and metabolic dysfunction–associated steatotic liver disease (MASLD). The endo-lysosomal system plays a central role in cholesterol uptake and intracellular trafficking, yet the molecular mechanisms governing these processes remain poorly understood. Here, we identify hepatic vacuolar protein sorting 35 (VPS35), a core component of the retromer complex, as a critical regulator of hepatocellular and systemic cholesterol homeostasis. Liver-specific VPS35 ablation in mice elevated plasma and hepatic cholesterol levels due to impaired hepatic uptake of atherogenic lipoproteins, defective cholesterol trafficking through the endo-lysosomal system, and increased de novo cholesterol biosynthesis. The decreased hepatic uptake of atherogenic lipoproteins was associated with altered subcellular distribution of the low-density lipoprotein receptor (LDLR) and reduced levels of LDLR-related protein 1 (LRP1). The increased hepatic cholesterol content was associated with altered lysosomal ultrastructure and pH and decreased levels of a wide range of lysosomal proteins, including key proteins for lysosomal cholesterol egress, such as lysosomal acid lipase (LAL), scavenger receptor class B member 2 (SCARB2), Niemann–Pick type C1 (NPC1), and NPC2. Collectively, these findings reveal a previously unrecognized function of the hepatic retromer complex in systemic cholesterol homeostasis. Beyond its established role in endosomal cargo transport, VPS35 is essential for lysosomal cholesterol handling by preserving key proteins involved in lysosomal cholesterol metabolism.
SN - 2212-8778
ER -