A liver-heart endocrine axis revealed by systems genetics and mediated by hepatocyte growth factor activator
Juda, M.; Sarver, D.; Cheng, J.; Hilser, J. R.; Li, X. S.; Yokota, T.; Li, C.; Pan, C.; Zhou, Z.; Arrieta, A.; Seldin, M.; Yang, X.; Tang, W. W.; Vondriska, T. M.; Hazen, S. L.; Allayee, H.; Lusis, A. J.
Show abstract
The liver and heart are tightly interconnected organs, and liver disease is frequently accompanied by cardiovascular dysfunction, including heart failure1-5. Despite this clinical association, the mechanisms by which liver-derived endocrine signals influence cardiac gene programs and disease susceptibility remain poorly defined. Inter-organ endocrine communication is increasingly recognized as a key regulator of systemic physiology, including cardiac function6-8, but a comprehensive understanding of liver-heart communication is lacking. Here we use an unbiased, population-based systems genetics approach in a genetically diverse mouse cohort to identify liver-derived secreted factors associated with cardiac transcriptomic variation. This analysis reveals hepatocyte growth factor activator (HGFAC) as a candidate mediator of inter-organ communication. Cross-tissue analysis of human genetic and transcriptomic datasets further suggests a conserved relationship between hepatic HGFAC expression and cardiac gene programs. These observations implicate a previously unrecognized liver-heart axis that appears to contribute to heart failure pathophysiology across species.
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