Objectives

Cholestatic liver diseases are characterized by hepatocellular damage, cholangiocyte proliferation, and progressive fibrosis. Bile duct ligation (BDL) is widely used to resemble liver injuries induced by cholestasis. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α) was reported to play a critical role in multiple biological responses. Nevertheless, whether PGC1α is involved in bile acid metabolism and biliary disorders remains unclear. This study aimed to investigate the effect of PGC1α on hepatic responses after cholestatic injury.

Materials and methods

Wild-type mice were subjected to BDL or sham surgery for 14 days and human liver specimens from patients with primary biliary cholangitis (PBC) were collected to detect the expression of PGC1α. Hepatic-specific PGC1α knockout mice (HKO) were constructed and subjected to BDL, in which the effects of PGC1α on cholestatic liver injury were demonstrated by biochemical and histopathological assessments, immunoblotting, and metabolomics.

Results

The expression of PGC1α was upregulated in the liver of PBC patients and murine models. Both in vivo and in vitro experiments supported the protective effects of PGC1α on cholestasis-induced hepatocyte injury. Infiltrated inflammatory cells after BDL were decreased in HKO mice. Inhibited Wnt/β-Catenin pathway and enhanced Notch signaling promoted transdifferentiation of hepatic progenitor cells (HPC)/ hepatocytes into cholangiocytes, leading to the greater ductular reaction observed in the HKO mice. But bile acids metabolism and mitochondrial function were not affected due to hepatic PGC1α deficiency in cholestasis.

Conclusions

Hepatic-specific deletion of PGC1α regulated liver regeneration by promoting ductular reactions, thereby exerting protective effects against BDL-induced liver injury, which could be a new potential therapeutic target.

中文翻译：

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PGC1α缺乏通过减轻肝脏炎症和促进胆管重塑来逆转胆汁淤积引起的肝损伤

目标

胆汁淤积性肝病的特征是肝细胞损伤、胆管细胞增殖和进行性纤维化。胆管结扎（BDL）广泛用于模拟胆汁淤积引起的肝损伤。据报道，过氧化物酶体增殖物激活受体-γ 共激活物 1 α (PGC1α) 在多种生物反应中发挥着关键作用。然而，PGC1α是否参与胆汁酸代谢和胆道疾病仍不清楚。本研究旨在探讨PGC1α对胆汁淤积性损伤后肝脏反应的影响。

材料和方法

对野生型小鼠进行BDL或假手术14天，并采集原发性胆汁性胆管炎（PBC）患者的人肝脏标本检测PGC1α的表达。构建肝脏特异性 PGC1α 敲除小鼠(HKO) 并进行 BDL，通过生化和组织病理学评估、免疫印迹和代谢组学证明 PGC1α 对胆汁淤积性肝损伤的影响。

结果

PBC 患者和小鼠模型的肝脏中 PGC1α 的表达上调。体内和体外实验均支持 PGC1α 对胆汁淤积引起的肝细胞损伤的保护作用。HKO 小鼠 BDL 后浸润的炎症细胞减少。抑制 Wnt/β-Catenin 通路和增强 Notch 信号传导促进肝祖细胞 (HPC)/肝细胞转分化为胆管细胞，导致在 HKO 小鼠中观察到更大的导管反应。但胆汁酸代谢和线粒体功能并未因胆汁淤积时肝脏PGC1α缺乏而受到影响。

结论

肝脏特异性删除PGC1α通过促进导管反应来调节肝再生，从而对BDL引起的肝损伤发挥保护作用，这可能是一个新的潜在治疗靶点。