(W1272) Dysregulation of methionine metabolism of hepatocytes induced epithelial-mesenchymal transition of hepatocytes and abnormal growth of cholangiocytes in biliary atresia
Abstract: Biliary atresia (BA) is the most prevalent serious neonatal biliary obstructive disorder characterized by rapidly progressive biliary and liver fibrosis. However, the patho-mechanisms underlying the disease initiation and progression of BA are not known. A heterozygous de novo G to A mutation in exon 8 of the MAT1A gene was identified in a BA patient, which generated a frameshift and a premature stop codon. The mutant MAT was prone to degradation, and the level of MAT in patient’s liver was only 70% of that in normal control livers. MAT1A gene encodes Methionine adenosyltransferase enzyme 1A in hepatocytes, which catalyzes the biosynthesis of S-adenosylmethionine (SAMe) from methionine and ATP. Pluripotent stem cells (PSCs) generated from this patient’s peripheral blood (BA638C) exhibited an epithelial-mesenchymal transition (EMT) during hepatocyte differentiation, accompanied by mitochondrial membrane potential disruption and elevation of oxidative stress. These effects could be reversed by supplementing SAMe and glutathione, or by MG132, which inhibited the mutant MAT degradation. When healthy control PSC-derived cholangiocyte organoids were co-cultured with BA638C PSC-derived hepatocytes, their growth was inhibited, resulting in fewer and smaller organoids. Additionally, organoids exhibited altered morphology and elevated expression of hepatic marker genes. Bulk RNA sequencing of the organoids revealed cell cycle arrest, reduced proliferation, and stress response, with transcriptomics resembling those of BA liver tissue-derived organoids. In conclusion, this study indicates that (i) the MAT1A mutation induced EMT-like behavior of hepatocytes, potentially promoting liver fibrosis in disease progression; (ii) patients’ hepatocytes induced abnormal cholangiocyte development, which suggests that hepatocyte metabolic dysfunction can induce cholangiocyte/bile duct injury in the disease initiation of BA.
Funding Source: Theme-based Research Scheme (T12-712/21-R) RGC Hong Kong SAR Government, Hong Kong SAR, China
