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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Cholangiocyte autophagy contributes to hepatic cystogenesis in polycystic liver disease and represents a potential therapeutic target
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Cholangiocyte autophagy contributes to hepatic cystogenesis in polycystic liver disease and represents a potential therapeutic target

机译：Cholangiocyte自噬在多囊肝病中有助于肝脏囊肿，并且代表潜在的治疗靶标

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摘要

Polycystic liver disease (PLD) is a group of genetic disorders with limited treatment options and significant morbidity. Hepatic cysts arise from cholangiocytes exhibiting a hyperproliferative phenotype. Considering that hyperproliferation of many cell types is associated with alterations in autophagy, we hypothesized that autophagy is altered in PLD cholangiocytes, contributes to hepatic cystogenesis, and might represent a potential therapeutic target. We employed functional pathway cluster analysis and next‐generation sequencing, transmission electron microscopy, immunofluorescence confocal microscopy, and western blotting to assess autophagy in human and rodent PLD cholangiocytes. A three‐dimensional culture model was used to study the effects of molecular and pharmacologic inhibition of autophagy on hepatic cystogenesis in vitro , and the polycystic kidney disease–specific rat, an animal model of PLD, to study the effects of hydroxychloroquine, a drug that interferes with the autophagy pathway, on disease progression in vivo . Assessment of the transcriptome of PLD cholangiocytes followed by functional pathway cluster analysis revealed that the autophagy–lysosomal pathway is one of the most altered pathways in PLD. Direct evaluation of autophagy in PLD cholangiocytes both in vitro and in vivo showed increased number and size of autophagosomes, lysosomes, and autolysosomes; overexpression of autophagy‐related proteins (Atg5, Beclin1, Atg7, and LC3); and enhanced autophagic flux associated with activation of the cAMP–protein kinase A–cAMP response element–binding protein signaling pathway. Molecular and pharmacologic intervention in autophagy with ATG7 small interfering RNA, bafilomycin A 1 , and hydroxychloroquine reduced proliferation of PLD cholangiocytes in vitro and growth of hepatic cysts in three‐dimensional cultures. Hydroxychloroquine also efficiently inhibited hepatic cystogenesis in the polycystic kidney disease–specific rat. Conclusion: Autophagy is increased in PLD cholangiocytes, contributes to hepatic cystogenesis, and represents a potential therapeutic target for disease treatment. (H epatology 2018;67:1088–1108)
机译：多囊肝病（PLD）是一组遗传障碍，治疗方案有限，发病率显着。肝脏囊肿来自表现出过度增殖的表型的胆管细胞。考虑到许多细胞类型的过度增殖与自噬的变化相关，我们假设自噬在PLD胆管细胞中改变，有助于肝脏囊性发生，并且可能代表潜在的治疗靶标。我们使用功能性途径聚类分析和下一代测序，透射电子显微镜，免疫荧光共聚焦显微镜，以及西部印迹，以评估人和啮齿动物PLD胆管细胞的自噬。三维培养模型用于研究分子和药物抑制自噬对肝脏囊性发生的影响，以及PLD的动物模型，研究羟氯喹，一种药物的血糖肾病特异性大鼠干扰自噬途径，体内疾病进展。对PLD胆管细胞的转录组的评估随后具有功能性途径聚类分析显示，自噬溶酶体途径是PLD中最改变的途径之一。在体外和体内直接评估PLD胆管细胞中的自噬均显示出血糖，溶酶体和自糖的数量和大小增加;无引起自噬相关蛋白质（ATG5，BECLIN1，ATG7和LC3）;和增强与阵营蛋白激酶A-CAMP响应元结合蛋白信号传导途径的激活相关的自噬助体。用ATG7小干扰RNA，BafiLomycin A 1和羟基氯喹对自噬的分子和药理学干预在三维培养物中减少了PLD胆管细胞的增殖和生长。羟基氯喹还有有效地抑制多囊肾疾病特异性大鼠中的肝脏囊泡。结论：PLD胆管细胞中的自噬增加，有助于肝脏囊性发生，代表潜在的疾病治疗靶标。 （2018年Hopatology; 67：1088-1108）

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