Comprehensive Multiomic Analysis Reveals Metabolic Reprogramming Underlying Human Fontan-Associated Liver Disease

Area of Science:

• Cardiovascular Biology
• Hepatology
• Genomics and Proteomics

Background:

• The Fontan operation is standard for single-ventricle congenital heart disease, but frequently leads to Fontan-associated liver disease (FALD).
• The underlying mechanisms and effective treatments for FALD remain poorly understood.
• This study aimed to elucidate FALD pathogenesis through comprehensive multiomic analysis.

Purpose of the Study:

• To investigate the molecular mechanisms of Fontan-associated liver disease (FALD) using a multiomic approach.
• To identify key metabolic pathways and molecular players involved in FALD pathogenesis.
• To establish a comprehensive multiomic atlas of human FALD.

Main Methods:

• Applied untargeted liquid chromatography-mass spectrometry-based metabolomics to liver biopsies from FALD patients and controls.
• Integrated metabolomics data with existing single-nucleus multiomic RNA sequencing and ATAC-seq data from FALD livers.
• Performed comparative analyses with serum metabolomics and data from other liver diseases.

Main Results:

• Discovered significant metabolic abnormalities in FALD livers, including altered amino acid metabolism, peroxisomal fatty acid oxidation, and bile acid metabolism.
• Integrated multiomic analyses revealed potential mechanisms driving these metabolic changes.
• Identified dysregulated amino acid metabolism as a commonality between FALD and metabolic dysfunction-associated fatty liver disease/steatohepatitis.

Conclusions:

• Comprehensive multiomic analyses provide novel insights into the fundamental biology of human FALD.
• The findings highlight significant metabolic reprogramming as a key feature of FALD.
• This research lays the groundwork for understanding FALD pathogenesis and developing targeted therapies.