Dhcr24, also known as 3β-hydroxysterol-Δ24 reductase, is a key enzyme in cholesterol synthesis, catalyzing the conversion of desmosterol to cholesterol [3,7]. It plays a crucial role in maintaining cholesterol homeostasis, which is essential for various biological processes, and is involved in multiple signaling pathways, such as the LXRα pathway [1,4,5]. Cholesterol is not only a structural component of cells but also a precursor for various active substances regulating cell signaling pathways [2].

In animal models, inhibition of Dhcr24 by SH42 in APOE*3-Leiden.CETP mice increased desmosterol levels, reduced hepatic lipid content, steatosis score, plasma fatty acid and cholesteryl ester concentrations, and decreased liver inflammation by preventing Kupffer cell activation and monocyte infiltration in an LXRα -dependent manner, suggesting a potential therapeutic strategy for NAFLD/NASH [1]. In TREM2 KO mice, the expression of Dhcr24 increased after traumatic brain injury, and TREM2 was shown to inhibit Dhcr24 and upregulate members of the LXR pathway, indicating TREM2 may alleviate white matter injury possibly through the Dhcr24/LXR pathway [4]. In endothelium-specific Dhcr24 knockout mice, there was increased endothelial cell senescence and endothelial dysfunction, characterized by changes in markers and impaired functions, suggesting Dhcr24 is essential in endothelial cell senescence [6].

In conclusion, Dhcr24 is vital for cholesterol homeostasis and impacts various biological processes. Gene-knockout mouse models have revealed its role in diseases like NAFLD/NASH, traumatic brain injury-related white matter injury, and endothelial cell senescence, providing valuable insights into disease mechanisms and potential therapeutic targets.

References:

1. Zhou, Enchen, Ge, Xiaoke, Nakashima, Hiroyuki, Giera, Martin, Wang, Yanan. 2023. Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation. In EMBO molecular medicine, 15, e16845. doi:10.15252/emmm.202216845. https://pubmed.ncbi.nlm.nih.gov/37357756/

2. Fu, Xin, Wang, Zhaosong. . DHCR24 in Tumor Diagnosis and Treatment: A Comprehensive Review. In Technology in cancer research & treatment, 23, 15330338241259780. doi:10.1177/15330338241259780. https://pubmed.ncbi.nlm.nih.gov/38847653/

3. Bai, Xiaojing, Mai, Meiting, Yao, Kai, Yuan, Xiangshan, Zu, Hengbing. 2022. The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis. In Acta neuropathologica communications, 10, 35. doi:10.1186/s40478-022-01338-3. https://pubmed.ncbi.nlm.nih.gov/35296367/

4. Li, Zhao, Yu, Shenghui, Li, Lin, Sun, Xiaochuan, Yan, Jin. . TREM2 alleviates white matter injury after traumatic brain injury in mice might be mediated by regulation of DHCR24/LXR pathway in microglia. In Clinical and translational medicine, 14, e1665. doi:10.1002/ctm2.1665. https://pubmed.ncbi.nlm.nih.gov/38649789/

5. Ge, Xiaoke, Slütter, Bram, Lambooij, Joost M, Wang, Yanan, Schönke, Milena. 2024. DHCR24 inhibitor SH42 increases desmosterol without preventing atherosclerosis development in mice. In iScience, 27, 109830. doi:10.1016/j.isci.2024.109830. https://pubmed.ncbi.nlm.nih.gov/38770137/

6. Li, Han, Yang, Zhen, Liang, Wukaiyang, Yan, Jinhua, Zhang, Cuntai. . DHCR24 Insufficiency Promotes Vascular Endothelial Cell Senescence and Endothelial Dysfunction via Inhibition of Caveolin-1/ERK Signaling. In The journals of gerontology. Series A, Biological sciences and medical sciences, 79, . doi:10.1093/gerona/glae059. https://pubmed.ncbi.nlm.nih.gov/38407305/

7. Zerenturk, Eser J, Sharpe, Laura J, Ikonen, Elina, Brown, Andrew J. 2013. Desmosterol and DHCR24: unexpected new directions for a terminal step in cholesterol synthesis. In Progress in lipid research, 52, 666-80. doi:10.1016/j.plipres.2013.09.002. https://pubmed.ncbi.nlm.nih.gov/24095826/