Morón-Ros Samantha, Blasco-Roset Albert, Navarro-Gascon Artur, Rupérez Celia, Zamora Monica, Crispi Fatima, Uriarte Iker, Fernández-Barrena Maite G, Avila Matias, Ferrer-Curriu Gemma, Lupón Josep, Bayés-Genis Antoni, Villarroya Francesc, Gavaldà-Navarro Aleix, Planavila Anna
Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain.
Fetal i+D Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clinic and Hospital San Juan de Deu), Institut Clinic de Ginecologia, Obstetricia i Neonatalogia, Institut d'Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
J Pathol. 2023 Nov;261(3):335-348. doi: 10.1002/path.6193. Epub 2023 Aug 31.
FGF15 and its human orthologue, FGF19, are members of the endocrine FGF family and are secreted by ileal enterocytes in response to bile acids. FGF15/19 mainly targets the liver, but recent studies indicate that it also regulates skeletal muscle mass and adipose tissue plasticity. The aim of this study was to determine the role(s) of the enterokine FGF15/19 during the development of cardiac hypertrophy. Studies in a cohort of humans suffering from heart failure showed increased circulating levels of FGF19 compared with control individuals. We found that mice lacking FGF15 did not develop cardiac hypertrophy in response to three different pathophysiological stimuli (high-fat diet, isoproterenol, or cold exposure). The heart weight/tibia length ratio and the cardiomyocyte area (as measures of cardiac hypertrophy development) under hypertrophy-inducing conditions were lower in Fgf15-null mice than in wild-type mice, whereas the levels of the cardiac damage marker atrial natriuretic factor (Nppa) were up-regulated. Echocardiographic measurements showed similar results. Moreover, the genes involved in fatty acid metabolism were down-regulated in Fgf15-null mice. Conversely, experimental increases in FGF15 induced cardiac hypertrophy in vivo, without changes in Nppa and up-regulation of metabolic genes. Finally, in vitro studies using cardiomyocytes showed that FGF19 had a direct effect on these cells promoting hypertrophy. We have identified herein an inter-organ signaling pathway that runs from the gut to the heart, acts through the enterokine FGF15/19, and is involved in cardiac hypertrophy development and regulation of fatty acid metabolism in the myocardium. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
成纤维细胞生长因子15（FGF15）及其人类同源物成纤维细胞生长因子19（FGF19）是内分泌FGF家族的成员，由回肠肠细胞响应胆汁酸分泌。FGF15/19主要作用于肝脏，但最近的研究表明，它还调节骨骼肌质量和脂肪组织可塑性。本研究的目的是确定肠因子FGF15/19在心肌肥大发展过程中的作用。对一组心力衰竭患者的研究表明，与对照组相比，他们循环中的FGF19水平升高。我们发现，缺乏FGF15的小鼠在三种不同的病理生理刺激（高脂饮食、异丙肾上腺素或冷暴露）下不会发生心肌肥大。在诱导肥大的条件下，Fgf15基因敲除小鼠的心脏重量/胫骨长度比值和心肌细胞面积（作为心肌肥大发展的指标）低于野生型小鼠，而心脏损伤标志物心钠素（Nppa）的水平上调。超声心动图测量结果相似。此外，Fgf1基因敲除小鼠中参与脂肪酸代谢的基因下调。相反，实验性增加FGF15可在体内诱导心肌肥大，而Nppa无变化，代谢基因上调。最后，使用心肌细胞的体外研究表明，FGF19对这些细胞有直接促进肥大的作用。我们在此确定了一条从肠道到心脏的器官间信号通路，该通路通过肠因子FGF15/19发挥作用，参与心肌肥大的发展和心肌脂肪酸代谢的调节。© 2023作者。《病理学杂志》由约翰·威利父子有限公司代表大不列颠及爱尔兰病理学会出版。
