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Single-cell Spatial Transcriptomics Reveals Hepatocyte Metabolic Reprogramming in Fontan Associated Liver Disease

ABSTRACT: Background: Fontan-associated liver disease (FALD) is a common sequelae of single-ventricle patients palliated with the Fontan operation. FALD severity can impact clinical decisions; however, the pathophysiology of FALD progression is unknown. Methods: Single-cell spatial transcriptomics (ST) was performed on liver explant tissue sections from FALD patients with early and advanced fibrosis using CosMxTM Spatial Molecular Imaging with in-situ hybridization of 6000 genes (n=2). Immunofluorescence for hepatic zonation and cellular stress markers was used to confirm protein expression based on ST analysis in biopsy and explant FALD tissues (n=17). Results: Unbiased clustering yielded 12 liver cell types, comprising five subtypes of hepatocytes. FALD with advanced fibrosis demonstrated the expansion of mid-zonal hepatocytes, accompanied by the loss of metabolic markers associated with canonical pericentral and periportal hepatocytes. Advanced FALD hepatocytes uniquely demonstrated increased cellular stress and a redundant metabolic phenotype. Advanced FALD hepatocytes changed into a senescent-like state, which we have termed hepatocyte metabolic exhaustion. Protein expression analysis confirmed metabolic exhaustion within hepatocytes and upregulation of cellular stress markers in advanced FALD tissue specimens. Immunofluorescence staining of FALD samples demonstrated a disruption of zonation and a significant increase in heat shock protein 70 (HSP70). HSP70 expression strongly correlated with the congestive hepatic fibrosis (CHF) score. Conclusions: Single-cell ST has identified a population of hepatocytes with features of metabolic exhaustion and cellular stress unique to advanced FALD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310443 | GEO | 2026/02/04

REPOSITORIES: GEO

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Project description: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.

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Single-cell Spatial Transcriptomics Reveals Hepatocyte Metabolic Reprogramming in Fontan Associated Liver Disease

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