■由于胆汁酸(BA)池的组成对肝脏病理生理学有重大影响,我们研究了BA受体武田G蛋白偶联受体(TGR5)对其的调控,促进对BA过载的肝保护。
■野生型,总和肝细胞特异性TGR5敲除,和TGR5过表达的小鼠用于:正常的部分(66%)和89%的扩展肝切除术(EHs),熊去氧胆酸(UDCA)-或胆甾胺(CT)-丰富的饮食,胆管结扎术(BDL),富含胆酸(CA)的饮食,和TGR5激动剂(RO)治疗。因此,我们研究了TGR5对BA组成的影响,肝损伤,再生和生存。我们还对肠道微生物群(GM)和胆囊(GB)进行了分析。分析了接受大肝切除术的患者的肝BA组成。
■TGR5-KO超疏水性BA组合物与BA合成的改变没有直接关系,也不是TGR5-KOGM生态失调,由肝细胞特异性KO小鼠和共同住房实验支持,分别。GB膨胀的TGR5依赖性控制对BA组成至关重要,如通过包括RO治疗和/或胆囊切除术的实验所确定的。EH后TGR5-KO生存率低,与加重的胆管周围坏死和BA超负荷有关,通过将BA转向毒性较低的组合物(CT处理)而得到改善。在有或没有胆囊切除术的BDL或CA丰富的饮食后,我们发现GB扩张具有很强的TGR5依赖性肝保护特性。在患者中,更疏水性的肝BA成分与肝切除术后的不良结局相关.
■BA组合物对于小鼠和人类的肝脏保护至关重要。我们指出TGR5是BA谱的关键调节剂,因此在BA超负荷条件下是潜在的肝保护靶标。
■通过小鼠体内多种实验方法,加上一项病人研究,这项工作为胆道稳态之间的关系带来了一些新的亮点,胆囊功能,和肝脏保护。我们发现肝脏胆汁酸成分对于最佳的肝脏修复至关重要,不仅在老鼠身上,但也在人类患者接受大的肝切除术。
UNASSIGNED: As the composition of the bile acid (BA) pool has a major impact on liver pathophysiology, we studied its regulation by the BA receptor Takeda G protein coupled receptor (TGR5), which promotes hepatoprotection against BA overload.
UNASSIGNED: Wild-type, total and hepatocyte-specific TGR5-knockout, and TGR5-overexpressing mice were used in: partial (66%) and 89% extended hepatectomies (EHs) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (CA)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied the impact of TGR5 on: BA composition, liver injury, regeneration and survival. We also performed analyses on the gut microbiota (GM) and gallbladder (GB). Liver BA composition was analysed in patients undergoing major hepatectomy.
UNASSIGNED: The TGR5-KO hyperhydrophobic BA composition was not directly related to altered BA synthesis, nor to TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and co-housing experiments, respectively. The TGR5-dependent control of GB dilatation was crucial for BA composition, as determined by experiments including RO treatment and/or cholecystectomy. The poor TGR5-KO post-EH survival rate, related to exacerbated peribiliary necrosis and BA overload, was improved by shifting BAs toward a less toxic composition (CT treatment). After either BDL or a CA-enriched diet with or without cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic liver BA composition was correlated with an unfavourable outcome after hepatectomy.
UNASSIGNED: BA composition is crucial for hepatoprotection in mice and humans. We indicate TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions.
UNASSIGNED: Through multiple in vivo experimental approaches in mice, together with a patient study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function, and liver protection. We showed that hepatic bile acid composition is crucial for optimal liver repair, not only in mice, but also in human patients undergoing major hepatectomy.