Intrahepatic cholestasis induced by drug toxicity may cause cholestatic hepatic injury (CHI) leading to liver fibrosis and cirrhosis. The G protein-coupled bile acid receptor 1 (TGR5) is a membrane receptor with well-known roles in the regulation of glucose metabolism and energy homeostasis. However, the role and mechanism of TGR5 in the context of inflammation during CHI remains unclear. Wild-type (WT) and TGR5 knockout (TGR5-/-) mice with CHI induced by bile duct ligation (BDL) were involved in vivo, and WT and TGR5-/- bone marrow-derived macrophages (BMDMs) were used in vitro. TGR5 deficiency significantly exacerbated BDL-induced liver injury, inflammatory responses and hepatic fibrosis compared with WT mice in vivo. TGR5-/- macrophages were more susceptible to lipopolysaccharide (LPS) stimulation than WT macrophages. TGR5 activation by its ligand suppressed LPS-induced pro-inflammatory responses in WT but not TGR5-/- BMDMs. Notably, expression of β-catenin was effectively inhibited by TGR5 deficiency. Furthermore, TGR5 directly interacted with Gsk3β to repress the interaction between Gsk3β and β-catenin, thus disrupting the β-catenin destruction complex. The pro-inflammatory nature of TGR5-knockout was almost abolished by lentivirus-mediated β-catenin overexpression in BMDMs. BMDM migration in vitro was accelerated under TGR5-deficient conditions or supernatant from LPS-stimulated TGR5-/- BMDMs. From a therapeutic perspective, TGR5-/- BMDM administration aggravated BDL-induced CHI, which was effectively rescued by β-catenin overexpression. Our findings reveal that TGR5 plays a crucial role as a novel regulator of immune-mediated CHI by destabilizing the β-catenin destruction complex, with therapeutic implications for the management of human CHI.

中文翻译：

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TGR5 的缺乏通过稳定 β-连环蛋白破坏复合物加剧了免疫介导的胆汁淤积性肝损伤。

药物毒性引起的肝内胆汁淤积可引起胆汁淤积性肝损伤（CHI），导致肝纤维化和肝硬化。G 蛋白偶联胆汁酸受体 1 (TGR5) 是一种膜受体，在调节葡萄糖代谢和能量稳态方面具有众所周知的作用。然而，TGR5 在 CHI 炎症背景下的作用和机制仍不清楚。野生型 (WT) 和 TGR5-/- 敲除 (TGR5-/-) 小鼠胆管结扎 (BDL) 诱导的 CHI 参与体内，WT 和 TGR5-/- 骨髓源性巨噬细胞 (BMDM) 用于体外. 与体内 WT 小鼠相比，TGR5 缺乏显着加剧了 BDL 诱导的肝损伤、炎症反应和肝纤维化。TGR5-/- 巨噬细胞比 WT 巨噬细胞更容易受到脂多糖 (LPS) 刺激。由其配体激活的 TGR5 可抑制 LPS 诱导的 WT 促炎反应，但不会抑制 TGR5-/- BMDMs。值得注意的是，β-连环蛋白的表达被 TGR5 缺陷有效抑制。此外，TGR5 直接与 Gsk3β 相互作用以抑制 Gsk3β 和 β-catenin 之间的相互作用，从而破坏 β-catenin 破坏复合物。BMDM 中慢病毒介导的 β- 连环蛋白过表达几乎消除了 TGR5 敲除的促炎性质。在 TGR5 缺陷条件或 LPS 刺激的 TGR5-/- BMDMs 的上清液中，体外 BMDM 迁移加速。从治疗的角度来看，TGR5-/- BMDM 给药加重了 BDL 诱导的 CHI，而 β-catenin 过表达有效地挽救了这种情况。