Beta-amyloid Deposition in Biliary Atresia Reduces Liver Regeneration by Inhibiting Energy Metabolism and Mammalian Target of Rapamycin Signaling.
Beta-amyloid Deposition in Biliary Atresia Reduces Liver Regeneration by Inhibiting Energy Metabolism and Mammalian Target of Rapamycin Signaling.
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DOI：
10.14309/ctg.0000000000000536
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发表时间：
2022-11-01
影响因子：
3.6
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中科院分区：
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胆道闭锁是一种新生儿常见的胆道梗阻性疾病。本研究旨在探讨β-淀粉样蛋白（Aβ）在BA发病中的作用及其机制。我们检测了Aβ蛋白及其前体在BA患者肝脏中的分布。建立了小鼠肝类器官和斑马鱼模型，以研究Aβ在BA肝再生中的确切作用。BA患儿肝组织中Aβ mRNA和蛋白表达均显著增加，并沉积于中央静脉周围。BA患者血浆中Aβ水平显著升高，且与肝损伤进展呈正相关。在体外，Aβ处理诱导异常形态并导致肝类器官生长受损。能量代谢分析表明，Aβ增加了类器官中的有氧糖酵解并减少了ATP合酶，其中哺乳动物靶向雷帕霉素信号被抑制。在体内，Aβ42暴露导致斑马鱼幼鱼肝脏变性。BA患儿肝脏中Aβ沉积通过减弱线粒体呼吸和哺乳动物靶向雷帕霉素信号而降低肝再生。
Biliary atresia (BA) is a devastating obstructive bile duct disease found in newborns. This study aims to investigate the roles and involved mechanisms of beta-amyloid (Aβ) in the pathogenesis of BA. We examined the distribution of Aβ protein and its precursor in the livers of patients with BA. A murine liver organoid and a zebrafish model were established to investigate the exact roles of Aβ in liver regeneration for BA. Both Aβ mRNA and protein significantly increased in livers of infants with BA and deposited around the central vein. In the plasma, Aβ elevated significantly in patients with BA and positively correlated with liver injury progression. In vitro, Aβ treatment induced abnormal morphology and caused impaired growth in liver organoids. Energy metabolism analysis demonstrated Aβ increased aerobic glycolysis and reduced ATP synthase in organoids, in which the mammalian target of rapamycin signaling was suppressed. In vivo, Aβ42 exposure caused liver degeneration in zebrafish larvae. Aβ depositing in livers of infants with BA reduced the liver regeneration through attenuating mitochondrial respiration and mammalian target of rapamycin signaling.