A comprehensive multiomic analysis reveals metabolic reprogramming underlying human Fontan-associated liver disease

ABSTRACT:

BACKGROUND: Single ventricle congenital heart disease (SVCHD) is a severe form of cardiac malformation in which there is only one functional ventricle. The Fontan operation is the current standard of care for SVCHD. Almost all patients who have undergone the Fontan operation develop liver fibrosis at a young age, resulting in a condition known as Fontan-associated liver disease (FALD). The pathogenesis and mechanisms underlying FALD remain little understood, hindering development of effective therapies.

OBJECTIVES: We aimed to present a comprehensive multiomic analysis of human FALD, thereby revealing the fundamental biology and pathogenesis of FALD.

METHODS: We recently generated a single-cell transcriptomic and epigenomic atlas of human FALD using snRNA-ATAC-seq, which revealed profound metabolic reprogramming in FALD. Here we applied liquid chromatography-mass spectrometry (LC-MS) based untargeted metabolomics to unveil the metabolomic landscape of human FALD, using liver samples/biopsies from age and gender-matched healthy donors and FALD patients (n=12 per group). Extracted liver metabolites were analyzed by C18 high performance liquid chromatography (HPLC) and hydrophilic interaction chromatography (HILIC) followed by high resolution MS on Orbitrap. Statistical and bioinformatics analyses were performed to identify altered metabolites and metabolic pathways in FALD. These results were integrated with recently published snRNA-ATAC-seq and serum metabolomics datasets to present a comprehensive multiomic atlas of FALD.

RESULTS: We discovered profound metabolic abnormalities in livers of patients with early-stage FALD, particularly amino acid metabolism, peroxisomal fatty acid oxidation, cytochrome P450 system, glycolysis, TCA cycle, ketone body metabolism and bile acids metabolism. Integrated analyses with liver snRNA-ATAC-seq and serum metabolomics data unveiled the transcriptional mechanisms driving this metabolic reprogramming and the crosstalk between liver and the rest of the body. Comparison with human metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatohepatitis (MASH) revealed dysregulated amino acid metabolism as a common metabolic abnormality.

CONCLUSIONS: Our comprehensive multiomic atlas of human FALD reveals the fundamental biology and pathogenesis mechanisms of FALD.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - positive - reverse phase, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS10782 | MetaboLights | 2024-12-13

REPOSITORIES: MetaboLights