Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
Shock. 2018 Sep;50(3):316-323. doi: 10.1097/SHK.0000000000001019.
The farnesoid X receptor (FXR) plays an important role in bile acid metabolism, intestinal homeostasis, and intestinal ischemia-reperfusion (I/R) injury. We aimed to clarify the potential effects of FXR on intestinal epithelial cell tolerance to intestinal I/R injury and reveal the underlying mechanisms. An intestinal I/R injury model was established by the occlusion of the superior mesenteric artery for ischemia for 1 h, followed by reperfusion for 4 h in C57BL/6 (wild type [WT]) and FXR mice. The small intestine injury was assessed by histological analysis. Diamine oxidase and TNF-α levels in the serum were measured. Expressions of Bcl-2, Bax, caspase-3, and cystathionine-γ-lyase (CSE) were determined by immunohostochemical staining. Oxygen-glucose deprivation/reperfusion (OGD/R) was used to make injury in cultured Caco-2 cells pretreated with FXR agonist (INT-747) or DL-propargylglycine (PAG) for 24 h. Cell viability and the expressions of NF-κB, TNF-α, and IL-6 were assessed. Compared with WT I/R mice, FXR knockout mice exacerbated intestinal I/R injury, intestinal epithelial apoptosis, and inflammatory response. The I/R injury in WT mice was alleviated with INT-747 pretreatment. CSE expression increased after intestinal I/R injury in WT but not in FXR mice. INT-747 enhanced Caco-2 cell viability and inhibited inflammatory response by blocking the NF-κB pathway after OGD/R injury, which was diminished by a CSE-specific inhibitor (PAG). Thus, we demonstrated that FXR activation enhances intestinal epithelial cell tolerance to I/R by suppressing the inflammatory response and NF-κB pathway via CSE mediation.
法尼醇 X 受体 (FXR) 在胆汁酸代谢、肠道内稳态和肠道缺血再灌注 (I/R) 损伤中发挥重要作用。我们旨在阐明 FXR 对肠道上皮细胞耐受肠道 I/R 损伤的潜在作用，并揭示其潜在机制。通过夹闭肠系膜上动脉缺血 1 小时，然后再灌注 4 小时，在 C57BL/6（野生型 [WT]）和 FXR 小鼠中建立肠道 I/R 损伤模型。通过组织学分析评估小肠损伤。测量血清中二胺氧化酶和 TNF-α 的水平。通过免疫组织化学染色测定 Bcl-2、Bax、caspase-3 和胱硫醚-γ-裂解酶 (CSE) 的表达。用氧葡萄糖剥夺/再灌注 (OGD/R) 处理预先用 FXR 激动剂 (INT-747) 或 DL-炔丙基甘氨酸 (PAG) 处理 24 小时的培养 Caco-2 细胞造成损伤。评估细胞活力和 NF-κB、TNF-α 和 IL-6 的表达。与 WT I/R 小鼠相比，FXR 敲除小鼠加重了肠道 I/R 损伤、肠道上皮细胞凋亡和炎症反应。WT 小鼠用 INT-747 预处理可减轻 I/R 损伤。WT 小鼠的 I/R 损伤后 CSE 表达增加，但 FXR 小鼠则没有。在 OGD/R 损伤后，INT-747 通过阻断 NF-κB 通路增强了 Caco-2 细胞的活力并抑制了炎症反应，而 CSE 特异性抑制剂 (PAG) 则减弱了这种作用。因此，我们证明 FXR 激活通过 CSE 介导抑制炎症反应和 NF-κB 通路增强肠道上皮细胞对 I/R 的耐受性。
