LXR调控25HC与25HC3S合成代谢平衡与抗病毒功能

25-Hydroxycholesterol (25HC) is the product synthesized from cholesterol by the action of cholesterol 25-hydroxylase (CH25H), and functions as an endogenous ligand for liver X receptor (LXR). 25HC has been demonstrated to have potent anti-viral properties to different types of virus. With the support by our previous grant for a young investigator from NSFC, so far, we have made substantial progress. We determined that 25HC is able to activate CH25H expression to increase 25HC production which implies the auto-regulatory mechanisms. In addition, we observed that expression of REPS2, a molecule might be involved in anti-viral infection, can be influenced by LXR and 25HC. Because 25HC can be further metabolized into 5-cholesten-3, 25-diol 3-sulfate (25HC3S) by sulfotransferase 2B1b (SLUT2B1b), we hypothesize that the homeostasis between 25HC and 25HC3S can play a critical role in anti-viral function of 25HC, as well as the role of 25HC in inflammation and immune responses. In current proposal, we suggest to complete the following studies. We will determine, 1) the expression of CH25H or SULT2B1b and the susceptibility of viral infection among different cell types, by which we can identify the correlation between 25HC/25HC3S and viral infection; 2) the effect of 25HC, 25HC3S and 25HC/25HC3S homeostasis on viral infection and related inflammation and immune response; 3) the effect of LXR on CH25H/SULT2B1b expression and 25HC/25HC3S production as well as viral infection; and 4) the effect of LXR ligands on REPS2 expression and its effect on LXR-inhibited viral infection. We believe that by completing the above studies, we are able to unveil the signaling pathways regulating 25HC synthesis/metabolism and the anti-viral actions. Our study can also advance our understandings in the field of immune regulation by cholesterol metabolism.

25-羟基胆固醇（25HC）是胆固醇25-羟化酶（CH25H）产物、LXR内源性配体，具有明确的抗病毒功能。在上一个青年项目支持下，我们发现25HC具有刺激CH25H表达、促进自合成调控机制；同时发现REPS2表达可能与LXR和25HC相关。25HC可被SULT2B1b磺酸化成25HC3S，但25HC3S具有与25HC不同的生物功能。因此，25HC与25HC3S之间的代谢平衡对25HC抗病毒功能至关重要。在本申请中我们将研究细胞CH25H、SULT2B1b表达水平与病毒感染之间的相互关系；检测25HC、25HC3S及二者代谢平衡对机体抗病毒感染和相关炎症与免疫反应的作用；LXR对CH25H、SULT2B1b表达与25HC/25HC3S代谢平衡的调控作用；LXR对REPS2的调控作用及与抗病毒关联性。通过我们的研究将揭示25HC合成代谢调控机理以及在抗病毒中的作用，促进代谢与免疫的发展。

病毒性疾病是困扰全球人类健康的重要难题，特别是随着新冠病毒的全球性流行，病毒性疾病的防治和相关机制的探索显得尤为重要。通过本项目的完成，我们确定：1）细胞CH25H和SULT2B1b表达水平与病毒感染难易相关，病毒感染不影响他们的表达和调控；2）25HC与25HC3S都能上调CH25H的表达，但是25HC3S作用较弱；3）激活25HC代谢降低其抗病毒功能；4）LXR激活能抑制HSV-1、MLV-(VSV)-GFP假型病毒和HBV的感染，可能具有广谱抗病毒功能；5）LXR激活调节25HC与25HC3S代谢平衡，当LXR激活后，25HC生成增多占主导；6）LXR靶向调控REPS2表达，25HC/5HC3S代谢平衡参与对LXR-REPS2表达的调控作用；7）REPS2可能通过调控受体内吞途径影响病毒入侵和复制。我们的研究全方位阐述了一类重要的核受体LXR在抗病毒中的作用和机制，通过调控羟基胆固醇的合成而起到广谱的抗病毒功能，将为抗病毒药物的开发提供重要参考。通过本项目的完成，我们在J Hepatol、Br J Pharmacol、Arterioscl Throm Vas Biol、J Biol Chem、J Lipid Res等本领域国际主流期刊上发表26篇论文；培养研究生1人，完成了预期研究目标。