2. Academic Validation
  3. A liver-heart endocrine axis revealed by systems genetics and mediated by hepatocyte growth factor activator

A liver-heart endocrine axis revealed by systems genetics and mediated by hepatocyte growth factor activator

  • medRxiv. 2026 May 6:2026.05.05.26352474. doi: 10.64898/2026.05.05.26352474.
Michal Juda 1 2,  Dylan Sarver 1,  Jenny Cheng 1 3,  James R Hilser 1,  Xinmin S Li 4,  Tomohiro Yokota 1 2 5,  Christopher Li 1,  Calvin Pan 1,  Zhiqiang Zhou 1,  Adrian Arrieta 6,  Marcus Seldin 7,  Xia Yang 2 3 8,  W H Wilson Tang 4 9,  Thomas M Vondriska 1 2 6,  Stanley L Hazen 4 9,  Hooman Allayee 1,  Aldons J Lusis 1 2 3 10 11
Affiliations

Affiliations

  • 1 Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
  • 2 Molecular Biology Institute, University of California, Los Angeles, CA 90095.
  • 3 Molecular, Cell, and Integrative Physiology Interdepartmental Ph.D Program, University of California, Los Angeles, CA 90095.
  • 4 Department of Heart Blood & Kidney Research, Cleveland Clinic Research, Cleveland, OH 44195.
  • 5 Department of Medicine, VA Greater Los Angeles Health Care System, Los Angeles, CA 90095.
  • 6 Department of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine at the University of California, Los Angeles.
  • 7 Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697.
  • 8 Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA.
  • 9 Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH 44195.
  • 10 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
  • 11 Department of Microbiology, Immunology, & Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
PMID: 42145616 DOI: 10.64898/2026.05.05.26352474
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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