Heart injury-induced Fibronectin 1 confers liver dysfunction in zebrafish through hepatic Pparβ signaling

Abstract

Organ–organ crosstalk mediated by secretory factors plays crucial roles in maintaining physiological homeostasis. Heart-related conditions, such as heart failure and cardiac ischemia/reperfusion, significantly impact liver pathogenesis, yet the exact molecular mechanisms remain unclear. Employing a zebrafish ventricular ablation model, we investigated the effects of heart injury (HI) on liver development and function. Our results revealed that HI stunted liver growth and induced aberrant lipid accumulation in zebrafish. Mechanistically, HI elevated cardiac and serum Fibronectin 1 (Fn1) protein levels and activated the hepatic integrin–Src axis, while reducing hepatic Ampkα phosphorylation and Pparβ abundance. Heart-specific Fn1 knockdown reversed these effects, ameliorating liver defects. Moreover, Ampkα activation via phosphorylation enhanced Pparβ and β-oxidation gene expression, whereas hepatic Pparβ knockdown abolished liver protection conferred by cardiac Fn1 reduction. Our study demonstrated that HI-induced stunted liver growth and aberrant lipid accumulation are conferred by cardiac-derived Fn1, which acts by suppressing hepatic Ampkα–Pparβ signaling. An in-depth understanding of the molecular mechanisms underlying inter-organ communication may provide new avenues for treating liver disorders induced by heart disease.

Keywords

Heart injury / Fibronectin 1 / Lipid accumulation / Liver stunted growth / Pparβ

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