Jin Dan, Lu Tianfei, Ni Ming, Wang Han, Zhang Jiang, Zhong Chenpeng, Shen Chuan, Hao Jun, Busuttil Ronald W, Kupiec-Weglinski Jerzy W, Zhang Jianjun, Xu Ning, Zhai Yuan
Department of Surgery David Geffen School of Medicine University of California Los Angles Los Angeles CA.
Department of Obstetrics and Gynecology and Shanghai Key Laboratory of Gynecologic Oncology Renji Hospital School of Medicine Shanghai Jiaotong University Shanghai China.
Hepatol Commun. 2020 Feb 13;4(4):540-554. doi: 10.1002/hep4.1478. eCollection 2020 Apr.
Farnesoid X receptor (FXR) is the nuclear receptor of bile acids and is involved in innate immune regulation. FXR agonists have been shown to protect multiple organs from inflammatory tissue injuries. Because liver expresses high levels of FXR, we explored the potential therapeutic benefits and underlying mechanisms of pharmacologic FXR activation in a murine model of partial liver warm ischemia. Pretreatment of mice with FXR agonist 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064) attenuated liver ischemia/reperfusion injuries (IRIs) in wild-type but not FXR knockout mice. Posttreatment with GW4064 facilitated liver recovery from IRI. Mechanistically, Kupffer cells (KCs) expressed much higher levels of FXR than bone marrow-derived macrophages (BMMs). Pretreatment of KCs but not BMMs with GW4064 resulted in lower tumor necrosis factor α but higher interleukin-10 expressions following toll-like receptor stimulation. FXR-targeted gene small heterodimer partner () was critical for the regulation of KC response by GW4064. , the depletion of KCs but not cluster of differentiation (CD) 11b cells or knockdown of diminished the immune regulatory effect of GW4064 in liver IRI. Thus, FXR activation protects liver from IRI by up-regulating in KCs to inhibit the liver proinflammatory response.
法尼酯X受体（FXR）是胆汁酸的核受体，参与固有免疫调节。FXR激动剂已被证明可保护多个器官免受炎症组织损伤。由于肝脏中FXR表达水平较高，我们在部分肝脏热缺血的小鼠模型中探索了药物性激活FXR的潜在治疗益处及潜在机制。用FXR激动剂3-（2,6-二氯苯基）-4-（3'-羧基-2-氯芪-4-基）氧甲基-5-异丙基异恶唑（GW4064）预处理小鼠可减轻野生型小鼠而非FXR基因敲除小鼠的肝脏缺血/再灌注损伤（IRI）。用GW4064进行后处理促进了肝脏从IRI中恢复。机制上，库普弗细胞（KC）中FXR的表达水平远高于骨髓来源的巨噬细胞（BMM）。用GW4064预处理KC而非BMM，在 toll样受体刺激后导致肿瘤坏死因子α表达降低但白细胞介素-10表达升高。FXR靶向基因小异二聚体伴侣（SHP）对于GW4064调节KC反应至关重要。此外，清除KC而非分化簇（CD）11b细胞或敲低SHP可减弱GW4064在肝脏IRI中的免疫调节作用。因此，激活FXR通过上调KC中的SHP来抑制肝脏促炎反应，从而保护肝脏免受IRI损伤。
