Sule Rasheed, Hu Po, Shoffler Clarissa, Petucci Christopher, Wilkins Benjamin J, Rychik Jack, Pei Liming
Center for Mitochondrial and Epigenomic Medicine Children's Hospital of Philadelphia Philadelphia PA USA.
Cardiovascular Institute, Children's Hospital of Philadelphia Philadelphia PA USA.
J Am Heart Assoc. 2025 Mar 18;14(6):e039201. doi: 10.1161/JAHA.124.039201. Epub 2025 Mar 7.
The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Almost all patients with Fontan operation develop liver fibrosis at a young age, known as Fontan-associated liver disease (FALD). The pathogenesis and mechanisms underlying FALD remain little understood, and there are no effective therapies. We aimed to present a comprehensive multiomic analysis of human FALD, revealing the fundamental biology and pathogenesis of FALD.
We recently generated a single-cell transcriptomic and epigenomic atlas of human FALD using single-nucleus multiomic RNA sequencing and assay for transposase-accessible chromatin using sequencing, which uncovered substantial metabolic reprogramming. Here, we applied liquid chromatography-mass spectrometry-based untargeted metabolomics to unveil the metabolomic landscape of human FALD, using liver samples/biopsies from age- and sex-matched donors and patients with FALD (n=12 per group). Results were integrated with liver single-nucleus multiomic RNA sequencing and assay for transposase-accessible chromatin using sequencing and serum metabolomics data to present a comprehensive multiomic atlas of FALD.We discovered significant metabolic abnormalities in livers of adolescent patients with Fontan circulation, particularly amino acid metabolism, peroxisomal fatty acid oxidation, cytochrome P450 system, glycolysis, tricarboxylic acid cycle, ketone body metabolism, and bile acid metabolism. Integrated analyses with liver single-nucleus multiomic RNA sequencing and assay for transposase-accessible chromatin using sequencing results unveiled potential underlying mechanisms of these metabolic changes. Comparison with serum metabolomics data indicate that liver metabolic reprogramming contributes to circulatory metabolomic changes in FALD. Furthermore, comparison with metabolomics data of human metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis highlighted dysregulated amino acid metabolism as a common metabolic abnormality.
Our comprehensive multiomic analyses reveal new insights into the fundamental biology and pathogenesis mechanisms of human FALD.
Fontan手术是目前单心室先天性心脏病的标准治疗方法。几乎所有接受Fontan手术的患者在年轻时都会发生肝纤维化，即Fontan相关肝病（FALD）。FALD的发病机制仍知之甚少，且尚无有效治疗方法。我们旨在对人类FALD进行全面的多组学分析，揭示FALD的基础生物学和发病机制。
我们最近使用单核多组学RNA测序和转座酶可及染色质测序分析生成了人类FALD的单细胞转录组和表观基因组图谱，发现了大量的代谢重编程。在此，我们应用基于液相色谱-质谱的非靶向代谢组学来揭示人类FALD的代谢组学特征，使用年龄和性别匹配的供体以及FALD患者的肝脏样本/活检组织（每组n = 12）。将结果与肝脏单核多组学RNA测序、转座酶可及染色质测序分析以及血清代谢组学数据相结合，呈现了FALD的全面多组学图谱。我们发现Fontan循环青少年患者的肝脏存在显著的代谢异常，特别是氨基酸代谢、过氧化物酶体脂肪酸氧化、细胞色素P450系统、糖酵解、三羧酸循环、酮体代谢和胆汁酸代谢。与肝脏单核多组学RNA测序和转座酶可及染色质测序分析结果的综合分析揭示了这些代谢变化的潜在机制。与血清代谢组学数据的比较表明，肝脏代谢重编程导致了FALD循环代谢组学的变化。此外，与人类代谢功能障碍相关脂肪性肝病和代谢功能障碍相关脂肪性肝炎的代谢组学数据比较突出了氨基酸代谢失调是一种常见的代谢异常。
我们的全面多组学分析揭示了人类FALD基础生物学和发病机制的新见解。
