25(R)-27-hydroxy Cholesterol

25(R)-27-hydroxy Cholesterol is an agonist of liver X receptor (LXR) α and LXRβ, with the EC₅₀ of 0.085 and 0.071μM, respectively^[1]. 25(R)-27-hydroxy Cholesterol, also known as (25R)-26-hydroxycholesterol or, 27-hydroxycholesterol, is the major stereoisomer of the endogenous oxygen sterol 27-hydroxycholesterol (comprising about 80% of the natural mixture)^[2]. 25(R)-27-hydroxycholesterol can impact the stability of cholesterol and has been widely used in studies on lipid metabolism control and regulation of the expression of genes related to inflammation^[3].

In vitro, 25(R)-27-hydroxy Cholesterol treatment 1μM at for 48 hours significantly promoted the proliferation of LNCaP cells and markedly increased their metabolic activity by activating the activity of estrogen receptor α (ERα)^[4]. Treatment with 5.6μM of 25(R)-27-hydroxy Cholesterol for 24 hours can inhibit human rhinovirus (HRV) infection in HeLa cells and reduce the markers of HRV replication^[5].

In vivo, 25(R)-27-hydroxy Cholesterol treatment (20mg/kg/day; s.c.) for 8 days increased the number of γδ-T cells and reduced cytotoxic T cells, promoting tumor progression in xenograft tumor mouse models^[6]. Before the dark cycle began, intraperitoneal injection of a single dose of 20mg/kg 25(R)-27-hydroxy Cholesterol resulted in a rapid decrease in food intake in both male and female C57BL/6J wild-type mice, and increased the inter-meal interval of female mice, the entire effect lasted for 6 hours^[7]. After 25(R)-27-hydroxy Cholesterol (5.5mg/kg/day) was administered by subcutaneous injections to APP/PS1 transgenic mice for 3 weeks, severe lesions occurred in the ileum and colon, and the integrity of the intestinal barrier was impaired, accompanied by the dilation of tight junctions and the downregulation of tight junction proteins (including occludin, tight junction protein 1, tight junction protein 5, and ZO-1) ^[8].

References:
[1] Fu X, Menke J G, Chen Y, et al. 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells[J]. Journal of Biological Chemistry, 2001, 276(42): 38378-38387.
[2] Javitt N B. 25R, 26-Hydroxycholesterol revisited: synthesis, metabolism, and biologic roles[J]. Journal of lipid research, 2002, 43(5): 665-670.
[3] Kim D, Lee K M, Lee C, et al. Pathophysiological role of 27-hydroxycholesterol in human diseases[J]. Advances in biological regulation, 2022, 83: 100837.
[4] Raza S, Meyer M, Goodyear C, et al. The cholesterol metabolite 27-hydroxycholesterol stimulates cell proliferation via ERβ in prostate cancer cells[J]. Cancer cell international, 2017, 17(1): 52.
[5] Civra A, Costantino M, Cavalli R, et al. 27-Hydroxycholesterol inhibits rhinovirus replication in vitro and on human nasal and bronchial histocultures without selecting viral resistant variants[J]. Antiviral Research, 2022, 204: 105368.
[6] Baek A E, Yu Y R A, He S, et al. The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells[J]. Nature communications, 2017, 8(1): 864.
[7] Ye H, Yang X, Feng B, et al. 27-Hydroxycholesterol acts on estrogen receptor α expressed by POMC neurons in the arcuate nucleus to modulate feeding behavior[J]. Science Advances, 2024, 10(28): eadi4746.
[8] Wang Y, An Y, Ma W, et al. 27-Hydroxycholesterol contributes to cognitive deficits in APP/PS1 transgenic mice through microbiota dysbiosis and intestinal barrier dysfunction[J]. Journal of neuroinflammation, 2020, 17(1): 199.

25(R)-27-hydroxy Cholesterol是肝脏X受体（LXR）α和LXRβ的激动剂，EC₅₀值分别为0.085μM和0.071μM^[1]。25(R)-27-hydroxy Cholesterol又称(25R)-26-羟基胆固醇或27-羟基胆固醇，是内源性氧固醇27-羟基胆固醇的主要立体异构体（约占天然混合物的80%）^[2]。25(R)-27-hydroxy Cholesterol能影响胆固醇稳定性，已广泛应用于脂质代谢调控及炎症相关基因表达研究^[3]。

在体外，1μM浓度的25(R)-27-hydroxy Cholesterol处理48小时可通过激活雌激素受体α（ERα）活性，显著促进LNCaP细胞增殖并增强细胞代谢活性^[4]。5.6μM浓度的25(R)-27-hydroxy Cholesterol处理24小时可抑制HeLa细胞中的人鼻病毒（HRV）感染，并降低HRV复制标志物水平^[5]。

在体内，以20mg/kg/day剂量的25(R)-27-hydroxy Cholesterol皮下给药 8天，可增加异种移植瘤小鼠模型中的γδ-T细胞数量并减少细胞毒性T细胞，促进肿瘤进展^[6]。暗周期开始前单次腹腔注射20mg/kg剂量的25(R)-27-hydroxy Cholesterol，可导致C57BL/6J野生型雄性和雌性小鼠摄食量快速下降，并延长雌鼠进食间隔期，整体效应持续6小时^[7]。向APP/PS1转基因小鼠皮下注射25(R)-27-hydroxy Cholesterol（5.5mg/kg/day）持续3周后，回肠和结肠出现严重病变，肠道屏障完整性受损，伴随紧密连接结构扩张及紧密连接蛋白（包括occludin、闭合蛋白1、闭合蛋白5和ZO-1）表达下调^[8]。