Ch25h, or cholesterol 25-hydroxylase, is a crucial gene involved in cholesterol metabolism. It converts cholesterol to 25-hydroxycholesterol (25HC), an oxysterol that participates in regulating cholesterol homeostasis, inflammation, and immune responses. The CH25H-CYP7B1-RORα axis of cholesterol metabolism in chondrocytes is a key catabolic regulator in osteoarthritis pathogenesis [1]. Also, CH25H is induced by IL-4 and IL-13 via STAT6, leading to 25HC accumulation and influencing macrophage immunosuppressive function [3].

In Ch25h-/-mice, cerebral ischemic stroke led to a significantly increased infarct volume, indicating that CH25H+ microglia have a neuroprotective role after stroke [2]. In NAFLD research, Ch25h knockout mice on a high-fat diet showed higher serum total cholesterol and triglyceride levels and were prone to hepatic steatosis, as Ch25h deficiency reduces cholesterol efflux regulated by LXRα, increases cholesterol synthesis mediated by SREBP-2, and activates the NLRP3 inflammasome [4].

In summary, Ch25h plays essential roles in cholesterol metabolism, inflammation, and immune responses. Gene knockout mouse models have revealed its significance in diseases such as cerebral ischemic stroke and NAFLD, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Choi, Wan-Su, Lee, Gyuseok, Song, Won-Hyun, Ryu, Je-Hwang, Chun, Jang-Soo. 2019. The CH25H-CYP7B1-RORα axis of cholesterol metabolism regulates osteoarthritis. In Nature, 566, 254-258. doi:10.1038/s41586-019-0920-1. https://pubmed.ncbi.nlm.nih.gov/30728500/

2. Zhang, Yueman, Guo, Yunlu, Li, Ruqi, Yu, Weifeng, Li, Peiying. 2023. Novel CH25H+ and OASL+ microglia subclusters play distinct roles in cerebral ischemic stroke. In Journal of neuroinflammation, 20, 115. doi:10.1186/s12974-023-02799-6. https://pubmed.ncbi.nlm.nih.gov/37183260/

3. Xiao, Jun, Wang, Shuang, Chen, Longlong, Wei, Bin, Wang, Hongyan. 2024. 25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages. In Immunity, 57, 1087-1104.e7. doi:10.1016/j.immuni.2024.03.021. https://pubmed.ncbi.nlm.nih.gov/38640930/

4. Wang, Yaqiong, Zhang, Jin, Chen, Jie, Li, Zhao, Lei, Ting. . Ch25h and 25-HC prevent liver steatosis through regulation of cholesterol metabolism and inflammation. In Acta biochimica et biophysica Sinica, 54, 504-513. doi:10.3724/abbs.2022030. https://pubmed.ncbi.nlm.nih.gov/35462473/