Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
BMC Gastroenterol. 2022 Aug 10;22(1):380. doi: 10.1186/s12876-022-02459-8.
Cholestatic liver diseases are a major source of morbidity and mortality that can progress to end-stage liver disease and hyperbilirubinemia is a hallmark of cholestasis. There are few effective medical therapies for primary biliary cholangitis, primary sclerosing cholangitis and other cholestatic liver diseases, in part, due to our incomplete understanding of the pathogenesis of cholestatic liver injury. The hepatic unfolded protein response (UPR) is an adaptive cellular response to endoplasmic reticulum stress that is important in the pathogenesis of many liver diseases and recent animal studies have demonstrated the importance of the UPR in the pathogenesis of cholestatic liver injury. However, the role of the UPR in human cholestatic liver diseases is largely unknown.
RNA was extracted from liver biopsies from patients after liver transplantation. RNA-seq was performed to determine the transcriptional profile and hepatic UPR gene expression that is associated with liver injury and cholestasis.
Transcriptome analysis revealed that patients with hyperbilirubinemia had enhanced expression of hepatic UPR pathways. Alternatively, liver biopsy samples from patients with acute rejection had enhanced gene expression of LAG3 and CDK1. Pearson correlation analysis of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin levels demonstrated significant correlations with the hepatic expression of several UPR genes, as well as genes involved in hepatic bile acid metabolism and inflammation. In contrast, serum alkaline phosphatase levels were correlated with the level of hepatic bile acid metabolism gene expression but not liver UPR gene expression.
Overall, these data indicate that hepatic UPR pathways are increased in cholestatic human liver biopsy samples and supports an important role of the UPR in the mechanism of human cholestatic liver injury.
胆汁淤积性肝病是导致发病率和死亡率的主要原因之一，可进展为终末期肝病，高胆红素血症是胆汁淤积的标志。原发性胆汁性胆管炎、原发性硬化性胆管炎和其他胆汁淤积性肝病的有效治疗方法很少，部分原因是我们对胆汁淤积性肝损伤的发病机制了解不完整。肝未折叠蛋白反应（UPR）是内质网应激的一种适应性细胞反应，在许多肝病的发病机制中很重要，最近的动物研究表明 UPR 在胆汁淤积性肝损伤的发病机制中很重要。然而，UPR 在人类胆汁淤积性肝病中的作用在很大程度上尚不清楚。
从肝移植后的患者肝活检中提取 RNA。进行 RNA-seq 以确定与肝损伤和胆汁淤积相关的转录谱和肝 UPR 基因表达。
转录组分析显示，高胆红素血症患者的肝 UPR 途径表达增强。相反，急性排斥反应患者的肝活检样本中 LAG3 和 CDK1 的基因表达增强。血清丙氨酸氨基转移酶、天冬氨酸氨基转移酶和总胆红素水平的 Pearson 相关性分析表明，与几种 UPR 基因以及参与肝胆汁酸代谢和炎症的基因的肝表达呈显著相关性。相比之下，血清碱性磷酸酶水平与肝胆汁酸代谢基因表达水平相关，但与肝 UPR 基因表达水平无关。
总的来说，这些数据表明，肝 UPR 途径在胆汁淤积性人类肝活检样本中增加，并支持 UPR 在人类胆汁淤积性肝损伤机制中的重要作用。
