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Publications

Journal Article Ahead of print

PubMed: 42457066 DOI: 10.1016/j.steroids.2026.109830

DHCR24 inhibition upregulates desmosterol without promoting regression of atherosclerotic plaques in APOE*3-Leiden.CETP mice.

Steroids

Authors: Jing Miao, Lobke F Zijlstra, Marieke Heijink, Iulia Sidorov, Jamie I van der Vaart, Christoph Müller, Franz Bracher, Menno P J de Winther, Martin Giera, Annette E Neele, Patrick C N Rensen, Sander Kooijman

Affiliations

  • Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands; Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
  • Amsterdam UMC, location University of Amsterdam, Department of Medical Biochemistry, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischemic Syndromes, Amsterdam, the Netherlands; Amsterdam Institute for Immunology and Infectious disease, Amsterdam, the Netherlands.
  • Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
  • Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
  • Department of Pharmacy, Center for Drug Research, Ludwig Maximilians University Munich, Munich, Germany.
  • Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.

Abstract

BACKGROUND AND AIMS

Inhibition of Δ24-dehydrocholesterol reductase (DHCR24) leads to accumulation of the cholesterol biosynthesis intermediate desmosterol, which is the endogenous ligand for liver X receptors (LXRs). Activation of LXRs is considered to be atheroprotective as it suppresses inflammation and stimulates cholesterol efflux in macrophages via upregulation of ATP-binding cassette transporters A1 and G1. In the current study we aimed to investigate the effect of the selective DHCR24 inhibitor SH42 on regression of atherosclerotic plaques in APOE*3-Leiden.CETP mice, a well-established model for human-like lipid metabolism.

METHODS

Mice were fed a Western-type diet (16% fat, 0.15% cholesterol) for 20 weeks to promote plaque development. Subsequently, treatment was started with vehicle or SH42 for 8 weeks while the animals were kept on a regular chow diet.

RESULTS

Treatment with SH42 significantly upregulated desmosterol levels in liver and plasma, and led to a small reduction in plasma triglyceride, nonHDL-cholesterol and HDL-cholesterol levels on top of the lipid-lowering effect caused by the dietary switch. While SH42 treatment did not affect immune cell numbers in blood, bone marrow, or spleen, SH42 strongly reduced the number of macrophages found in the peritoneum after thioglycolate injection.

CONCLUSIONS

While the dietary switch halted atherosclerotic lesion progression, SH42 treatment did not accelerate atherosclerotic lesion regression further.

MeSH

Macrophages, Desmosterol, Liver, Diet, Cholesterol, Therapeutics, Apolipoproteins E, Steroids, Plaque, Atherosclerotic, Plasma