Long-term Western diet feeding impairs hepatic vitamin D metabolism and promotes bone loss in mice

Authors

  • Pengcheng Zhou Siegfried Weller Institute for Trauma Research, Department of Trauma and Reconstructive Surgery, Eberhard-Karls-University Tuebingen, BG Unfallklinik, 72076 Tuebingen, Germany https://orcid.org/0009-0004-8678-2484
  • Mohammad Majd Hammour Siegfried Weller Institute for Trauma Research, Department of Trauma and Reconstructive Surgery, Eberhard-Karls-University Tuebingen, BG Unfallklinik, 72076 Tuebingen, Germany https://orcid.org/0009-0006-6679-2495
  • Romina H. Aspera-Werz Siegfried Weller Institute for Trauma Research, Department of Trauma and Reconstructive Surgery, Eberhard-Karls-University Tuebingen, BG Unfallklinik, 72076 Tuebingen, Germany https://orcid.org/0000-0002-5160-2111
  • Sabrina Ehnert Siegfried Weller Institute for Trauma Research, Department of Trauma and Reconstructive Surgery, Eberhard-Karls-University Tuebingen, BG Unfallklinik, 72076 Tuebingen, Germany https://orcid.org/0000-0003-4347-1702
  • Maiju Myllys Leibniz Research Centre for Working Environment and Human Factors (IfADo), 44139 Dortmund, Germany https://orcid.org/0000-0001-9117-4572
  • Zaynab Hobloss Leibniz Research Centre for Working Environment and Human Factors (IfADo), 44139 Dortmund, Germany https://orcid.org/0009-0003-8292-867X
  • Reham Hassan Leibniz Research Centre for Working Environment and Human Factors (IfADo), 44139 Dortmund, Germany; Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, Qena University, Qena, Egypt https://orcid.org/0000-0002-6569-7676
  • Daniela González Leibniz Research Centre for Working Environment and Human Factors (IfADo), 44139 Dortmund, Germany https://orcid.org/0000-0002-0092-1411
  • Rama Hendawi Leibniz Research Centre for Working Environment and Human Factors (IfADo), 44139 Dortmund, Germany; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, PO Box 7, Nablus, Palestine https://orcid.org/0009-0001-4435-691X
  • Karolina Edlund Leibniz Research Centre for Working Environment and Human Factors (IfADo), 44139 Dortmund, Germany https://orcid.org/0000-0002-0276-2143
  • Sandra Hans Institute for Clinical and Experimental Surgery, Saarland University, PharmaScienceHub (PSH), 66421 Homburg, Germany
  • Matthias W. Laschke Institute for Clinical and Experimental Surgery, Saarland University, PharmaScienceHub (PSH), 66421 Homburg, Germany https://orcid.org/0000-0002-7847-8456
  • Ahmed Ghallab Leibniz Research Centre for Working Environment and Human Factors (IfADo), 44139 Dortmund, Germany; Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, Qena University, Qena, Egypt https://orcid.org/0000-0003-0695-3403
  • Jan G. Hengstler Leibniz Research Centre for Working Environment and Human Factors (IfADo), 44139 Dortmund, Germany https://orcid.org/0000-0002-1427-5246
  • Andreas Nüssler Siegfried Weller Institute for Trauma Research, Department of Trauma and Reconstructive Surgery, Eberhard-Karls-University Tuebingen, BG Unfallklinik, 72076 Tuebingen, Germany. E-mail: Andreas.nuessler@gmail.com https://orcid.org/0000-0002-6666-6791
  • Tanja C. Maisenbacher Siegfried Weller Institute for Trauma Research, Department of Trauma and Reconstructive Surgery, Eberhard-Karls-University Tuebingen, BG Unfallklinik, 72076 Tuebingen, Germany https://orcid.org/0009-0002-5628-7875

DOI:

https://doi.org/10.17179/excli2025-9085

Keywords:

bone loss, osteoporosis, liver-bone axis, MAFLD, bone homeostasis, Vitamin D

Abstract

Obesity and metabolic dysfunction-associated fatty liver disease (MAFLD) are increasingly recognized as risk factors for skeletal fragility, yet the mechanisms linking these conditions to impaired bone health remain poorly defined. The liver is central to vitamin D homeostasis through 25-hydroxylation, while skeletal responsiveness relies on vitamin D receptor (VDR) signaling. Disruption of either process may compromise bone remodeling. In this study, we investigated the long-term effects of Western diet (WD) feeding on hepatic vitamin D metabolism and bone integrity in a mouse model. Male C57BL/6N mice were fed a standard diet (SD) or WD for 48 weeks. WD-fed mice developed obesity, hepatic injury, and trabecular bone deterioration characterized by reduced bone mineral density and increased trabecular separation. Although trabecular architecture was compromised, three-point bending revealed no significant impairment in cortical bone mechanical properties. Histological analyses showed increased bone marrow adiposity and macrophage/monocyte lineage cells. Bone gene expression profiling indicated enhanced osteoclastogenic signaling. Hepatic transcriptomics demonstrated marked downregulation of key 25-hydroxylases (Cyp2r1, Cyp27a1) and vitamin D–binding protein, accompanied by reduced circulating 25‑hydroxyvitamin D. Bone tissue also exhibited decreased VDR protein abundance. Together, these findings suggest that long-term WD-induced obesity and hepatic dysfunction impair hepatic vitamin D metabolism and diminish skeletal vitamin D responsiveness, contributing to bone fragility. Targeting the liver–bone axis and restoring vitamin D homeostasis may provide therapeutic potential for obesity-related bone loss.

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Published

2026-01-23

How to Cite

Zhou, P., Hammour, M. M., Aspera-Werz, R. H., Ehnert, S., Myllys, M., Hobloss, Z., … Maisenbacher, T. C. (2026). Long-term Western diet feeding impairs hepatic vitamin D metabolism and promotes bone loss in mice. EXCLI Journal, 25, 290–309. https://doi.org/10.17179/excli2025-9085

Issue

Vol. 25 (2026)

Section

Original articles

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Copyright (c) 2026 Pengcheng Zhou, Mohammad Majd Hammour, Romina H. Aspera-Werz, Sabrina Ehnert, Maiju Myllys, Zaynab Hobloss, Reham Hassan, Daniela González, Rama Hendawi, Karolina Edlund, Sandra Hans, Matthias W. Laschke, Ahmed Ghallab, Jan G. Hengstler, Andreas Nüssler, Tanja C. Maisenbacher

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