DHCR24 inhibitor SH42 increases desmosterol without preventing atherosclerosis development in mice.

Autor:	Ge X; Department of Medicine, Div. of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands., Slütter B; Div. of BioTherapeutics, Leiden Academic Center for Drug Research, Leiden University, Leiden 2333 AL, the Netherlands., Lambooij JM; Department of Parasitology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands., Zhou E; Department of Medicine, Div. of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands., Ying Z; Department of Medicine, Div. of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands., Agirman C; Department of Medicine, Div. of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands., Heijink M; The Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands., Rimbert A; Nantes Université, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France., Guigas B; Department of Parasitology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands., Kuiper J; Div. of BioTherapeutics, Leiden Academic Center for Drug Research, Leiden University, Leiden 2333 AL, the Netherlands., Müller C; Department of Pharmacy, Center for Drug Research, Ludwig Maximilians Universität München, 80539 Munich, Germany., Bracher F; Department of Pharmacy, Center for Drug Research, Ludwig Maximilians Universität München, 80539 Munich, Germany., Giera M; The Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands., Kooijman S; Department of Medicine, Div. of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands., Rensen PCN; Department of Medicine, Div. of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands., Wang Y; Department of Medicine, Div. of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.; 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., Schönke M; Department of Medicine, Div. of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2024 Apr 26; Vol. 27 (6), pp. 109830. Date of Electronic Publication: 2024 Apr 26 (Print Publication: 2024).
DOI:	10.1016/j.isci.2024.109830
Abstrakt:	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. Competing Interests: The authors declare no competing interests. (© 2024 The Author(s).)
Databáze:	MEDLINE
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