Effects of fibroblast growth factor 21 on the heart Pongpan Tanajak 1,2 , Siriporn C Chattipakorn 1,3,4 and Nipon Chattipakorn 1,2,3 1 Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, 2 Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, 3 Center of Excellence in Cardiac Electrophysiology Research, and 4 Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand Correspondence should be addressed to N Chattipakorn Email ncchattip@gmail.com Abstract Fibroblast growth factor 21 (FGF21) is a novel polypeptide ligand that has been shown to be involved in several physiological and pathological processes including regulation of glucose and lipids as well as reduction of arteriosclerotic plaque formation in the great vessels. It has also been shown to exert cardioprotective effects in myocardial infarction, cardiac ischemia- reperfusion injury, cardiac hypertrophy and diabetic cardiomyopathy. Moreover, FGF21 protects the myocardium and great arteries by attenuating remodeling, inflammation, oxidative stress and also promoting the energy supply to the heart through fatty acid b-oxidation. This growing evidence emphasizes the important roles of FGF21 in cardioprotection. This review comprehensively summarizes and discusses the consistent and inconsistent findings regarding the beneficial effects of FGF21 on the heart available from both basic research and clinical reports. The details of the signaling, biological and pharmacological effects of FGF21 with regard to its protection of the heart are also presented and discussed in this review. Key Words " fibroblast growth factor 21 " myocardial injury " cardiac metabolism " oxidative stress Journal of Endocrinology (2015) 227, R13–R30 Introduction Fibroblast growth factors (FGFs) are polypeptide chains that have paracrine, autocrine or endocrine functions. The paracrine FGFs are further divided into five subfamilies, whereas the autocrine and endocrine FGFs are composed of one subfamily each (Itoh & Ornitz 2011, Itoh & Ohta 2013)(Fig. 1). FGFs act through cell surface FGF receptors (FGFRs), which are regulated by four types of genes including FGFR1, FGFR2, FGFR3 and FGFR4 (Mohammadi et al. 2005, Beenken & Mohammadi 2009, Goetz & Mohammadi 2013). Although FGFRs are essential for FGF action on the target cells, they cannot activate intra- cellular signaling without co-receptors (Kharitonenkov 2008). Previous studies show that heparan sulphate proteoglycans are essential co-receptors for paracrine and autocrine FGFs (Beenken & Mohammadi 2009, Goetz & Mohammadi 2013), whereas Klothos are essential co-receptors for endocrine FGFs to mediate their attachment to and activation of target FGFRs (Suzuki et al. 2008, Beenken & Mohammadi 2009, Goetz & Mohammadi 2013). FGF21 is an endocrine FGF that consists of 209 amino acids. The FGF21 ligand is produced from several organs such as the liver and adipose tissue (Ito et al. 2000), skeletal muscle (Joki et al. 2015), and the heart (Nishimura et al. 2000, Kharitonenkov 2009, Planavila et al. 2013, Patel et al. 2014). To activate FGF21 signaling, FGF21 binds to FGFR1c with its C-terminus, and also with b-Klotho as its co-receptor with its N-terminus, to form the FGFR/ b-Klotho complex (Kharitonenkov 2008, Suzuki et al. 2008, Yie et al. 2009, Ding et al. 2012, Hale et al. 2012). Journal of Endocrinology Review P TANAJAK and others FGF21 and the heart 227 :2 R13–R30 http://joe.endocrinology-journals.org Ñ 2015 Society for Endocrinology DOI: 10.1530/JOE-15-0289 Printed in Great Britain Published by Bioscientifica Ltd. Downloaded from Bioscientifica.com at 05/23/2020 11:01:53PM via free access