Beta-amyloid Deposition in Biliary Atresia Reduces Liver Regeneration by Inhibiting Energy Metabolism and Mammalian Target of Rapamycin Signaling

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. DISCUSSION: Aβ depositing in livers of infants with BA reduced the liver regeneration through attenuating mitochondrial respiration and mammalian target of rapamycin signaling.