Hepato-cardiac interorgan communication controls cardiac hypertrophy via combined endocrine-autocrine FGF21 signaling
Fibroblast growth factor (FGF) 21 is a hormone produced mainly by the liver but also other organs, including the heart. Although FGF21 analogs are used for treating obesity and metabolic syndrome in humans, preclinical and clinical studies have elicited mixed results about whether prolonged FGF21 signaling is protective or detrimental for cardiac function. Based on our findings, showing elevated serum and cardiac FGF21 levels in humans with increased left ventricular afterload, we explore the involvement of FGF21 in cardiac hypertrophy. Our mouse studies reveal interorgan liver-heart crosstalk, which is controlled by an initial hepatic FGF21 release followed by the induction of cardiomyocyte (CM) FGF21 expression. Tissue-specific genetic ablation or anti-sense oligonucleotide-based inhibition of FGF21 shows that, in response to pressure overload, CM FGF21 upregulation is a critical event that is stimulated by liver-derived FGF21 and drives cardiac hypertrophy likely by interfering with cardioprotective oxytocin signaling. Conclusively, the hepato-cardiac FGF21-based signaling axis governs cardiac hypertrophy.
Authors
- Catherine A. Makarewich (ORCID: https://orcid.org/0000-0001-6907-4401)
- Georgios Siokatas (ORCID: https://orcid.org/0000-0002-6786-2575)
- Dipayan Chaudhuri (ORCID: https://orcid.org/0000-0003-0605-7334)
- Sobuj Mia
- Rajika Roy (ORCID: https://orcid.org/0000-0001-9394-3224)
- Maria E. Marketou (ORCID: https://orcid.org/0000-0003-1888-3430)
- Erhe Gao (ORCID: https://orcid.org/0000-0002-5151-7857)
- Rafailia Sidiropoulou
- Konstantinos Drosatos (ORCID: https://orcid.org/0000-0003-0903-834X)
- Konstantinos Fragkiadakis (ORCID: https://orcid.org/0000-0002-5342-5411)
- Eftychia Markopoulou
- Jeffery D. Molkentin (ORCID: https://orcid.org/0000-0002-3558-6529)
- Walter J. Koch (ORCID: https://orcid.org/0000-0002-8522-530X)
- Yasuhide Kuwabara (ORCID: https://orcid.org/0000-0002-9493-9494)
- Joel D. Schilling (ORCID: https://orcid.org/0000-0002-3884-1994)
- Erjola Rapushi
- Mahmoud Elesawy (ORCID: https://orcid.org/0009-0001-7799-9575)
- Matthew Hoffman (ORCID: https://orcid.org/0000-0003-2724-784X)
- Scott Blair
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- Washington University in St. Louis (US)
- Aristotle University of Thessaloniki (GR)
- University of Utah (US)
- University Hospital of Heraklion (GR)
- University of Cincinnati (US)
- Temple University (US)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-05-07
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102125
- Citations
- 4
- Primary Topic
- Fibroblast Growth Factor Research
- Type
- article
- Field-Weighted Citation Impact
- 3.22