DHCR24 inhibitor SH42 increases desmosterol without preventing atherosclerosis development in mice

Xiaoke Ge; Bram Slütter; Joost M Lambooij; Enchen Zhou; Zhixiong Ying; Ceren Agirman; Marieke Heijink; Antoine Rimbert; Bruno Guigas; Johan Kuiper; Christoph Müller; Franz Bracher; Martin Giera; Sander Kooijman; Patrick C N Rensen; Yanan Wang; Milena Schönke

doi:10.1016/j.isci.2024.109830

DHCR24 inhibitor SH42 increases desmosterol without preventing atherosclerosis development in mice

iScience. 2024 Apr 26;27(6):109830. doi: 10.1016/j.isci.2024.109830. eCollection 2024 Jun 21.

Authors

Xiaoke Ge¹, Bram Slütter², Joost M Lambooij^{3

4}, Enchen Zhou¹, Zhixiong Ying¹, Ceren Agirman¹, Marieke Heijink⁵, Antoine Rimbert⁶, Bruno Guigas³, Johan Kuiper², Christoph Müller⁷, Franz Bracher⁷, Martin Giera⁵, Sander Kooijman¹, Patrick C N Rensen¹, Yanan Wang^{1

8}, Milena Schönke¹

Affiliations

¹ Department of Medicine, Div. of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
² Div. of BioTherapeutics, Leiden Academic Center for Drug Research, Leiden University, Leiden 2333 AL, the Netherlands.
³ Department of Parasitology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
⁴ Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
⁵ The Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
⁶ Nantes Université, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France.
⁷ Department of Pharmacy, Center for Drug Research, Ludwig Maximilians Universität München, 80539 Munich, Germany.
⁸ Med-X institute, Center for Immunological and Metabolic Diseases, and Department of Endocrinology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an 710061, China.

Abstract

The liver X receptor (LXR) is considered a therapeutic target for atherosclerosis treatment, but synthetic LXR agonists generally also cause hepatic steatosis and hypertriglyceridemia. Desmosterol, a final intermediate in cholesterol biosynthesis, has been identified as a selective LXR ligand that suppresses inflammation without inducing lipogenesis. Δ24-Dehydrocholesterol reductase (DHCR24) converts desmosterol into cholesterol, and we previously showed that the DHCR24 inhibitor SH42 increases desmosterol to activate LXR and attenuate experimental peritonitis and metabolic dysfunction-associated steatotic liver disease. Here, we aimed to evaluate the effect of SH42 on atherosclerosis development in APOE∗3-Leiden.CETP mice and low-density lipoproteins (LDL) receptor knockout mice, models for lipid- and inflammation-driven atherosclerosis, respectively. In both models, SH42 increased desmosterol without affecting plasma lipids. While reducing liver lipids in APOE∗3-Leiden.CETP mice, and regulating populations of circulating monocytes in LDL receptor knockout mice, SH42 did not attenuate atherosclerosis in either model.

Keywords: Cardiovascular medicine; Cellular physiology; Molecular genetics;.