Distinct hepatic transcriptome changes point to impaired metabolic liver zonation and mitochondrial dysfunction in acute-on-chronic liver failure

Bulk-RNA sequencing and spatial transcriptomics were performed in liver specimens from patients with compensated cirrhosis, decompensated cirrhosis or ACLF undergoing liver transplantation. In addition, a detailed analysis of genes involved in energy metabolism and associated substrates was performed. Results: ACLF was associated with changes in the hepatic transcriptome, clearly distinct from compensated and decompensated cirrhosis.

Most strongly downregulated in ACLF were pathways involved in substrate metabolism and mitochondrial function, and – more specifically - ACLF was characterized by downregulation of multiple genes involved in glucose and amino acid metabolism. In line, spatial transcriptomics data revealed a breakdown of the functional liver zonation in ACLF, with decreasing proportions of hepatocytes specialized in gluconeogenesis/beta-oxidation.

BCKDK, which was strongly downregulated in ACLF, was identified as a potential candidate gene linking impaired metabolism of branched-chain amino acids with impaired glucose metabolism. Conclusion: ACLF is characterized by distinct changes in the hepatic transcriptome, which affect key pathways in substrate metabolism and mitochondrial function and are associated with a loss of the functional liver zonation. Downregulation of BCKDK in ACLF might be of particular interest, as it may integrate metabolism of branched-chained amino acids with impaired glucose metabolism and mitochondrial dysfunction.