TGR5 controls bile acid composition and gallbladder function to protect the liver from bile acid overload.
TGR5 controls bile acid composition and gallbladder function to protect the liver from bile acid overload.
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DOI：
10.1016/j.jhepr.2020.100214
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Tordjmann T
中科院分区：
文献类型：
--
作者：
Bidault-Jourdainne V;Merlen G;Glénisson M;Doignon I;Garcin I;Péan N;Boisgard R;Ursic-Bedoya J;Serino M;Ullmer C;Humbert L;Abdelrafee A;Golse N;Vibert E;Duclos-Vallée JC;Rainteau D;Tordjmann T
由于胆汁酸池的组成对肝脏的病理生理有重要影响，我们研究了BA受体武田G蛋白偶联受体(TGR5)对其的调节作用，TGR5促进了对BA超负荷的肝脏保护。野生型、全部和肝细胞特异性TGR5基因敲除和TGR5过表达的小鼠被用于：在正常、熊去氧胆酸(UDCA)或胆碱(CT)强化饮食、胆管结扎(BDL)、胆酸(CA)强化饮食和TGR5激动剂(RO)治疗的基础上进行部分(66%)和89%扩大肝切除术(EHS)。因此，我们研究了TGR5对BA组成、肝损伤、再生和存活的影响。我们还对肠道微生物区系(GM)和胆囊区系(GB)进行了分析。对肝大部切除术患者的肝脏BA成分进行了分析。TGR5-KO超疏水BA组成与BA合成改变没有直接关系，也与TGR5-KO GM失调没有直接关系，分别得到肝细胞特异性KO小鼠和共居实验的支持。依赖于TGR5的GB扩张控制对BA成分至关重要，这是由包括RO治疗和/或胆囊切除术在内的实验确定的。EH后较差的TGR5-KO存活率与胆管周围坏死加重和BA超负荷有关，通过将BA转向毒性较低的成分(CT治疗)而得到改善。在BDL或CA强化饮食加或不加胆囊切除术后，我们发现GB扩张剂具有强烈的TGR5依赖的肝脏保护特性。在患者中，疏水性较强的肝脏BA成分与肝切除术后的不良结果相关。BA的组成对小鼠和人类的肝脏保护至关重要。我们认为TGR5是BA分布的关键调节因子，因此在BA超负荷条件下是一个潜在的肝保护靶点。通过在小鼠身上的多种体内实验方法，以及一项患者研究，这项工作为胆汁动态平衡、胆囊功能和肝脏保护之间的关系带来了一些新的认识。我们发现，肝脏胆汁酸的组成对于最佳的肝脏修复至关重要，不仅在小鼠身上，而且在接受大范围肝切除的人类患者中也是如此。降低BA疏水性可改善小鼠大范围肝切除后的预后。BA受体TGR5控制BA池的组成，这对肝脏修复至关重要。TGR5以胆囊靶向起到保护肝脏的作用。在患者中，更疏水性的BA池与肝切除术后的肝损伤有关。
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. 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. 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. 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. 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. Reducing BA hydrophobicity improves outcomes after major hepatectomy in mice. The BA receptor TGR5 controls BA pool composition, which is crucial for liver repair. TGR5 targets the gallbladder to induce a hepatoprotective effect. In patients, a more hydrophobic BA pool is associated with liver injury after hepatectomy.
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