The protective effect of fibroblast growth factor‐21 in alcoholic cardiomyopathy: a role in protecting cardiac mitochondrial function

Abstract

Alcoholic cardiomyopathy (ACM) resulting from chronic alcohol misuse is one of the main contributors leading to heart failure and cardiovascular mortality. Fibroblast growth factor 21 (FGF21) is a well‐established cardioprotective factor. We aimed to study the role of FGF21 in experimentally induced models and clinical affected patients with cardiac damage due to chronic alcohol consumption. We found that circulating FGF21 levels and cardiac FGF21 and β‐klotho protein levels were increased in subjects with chronic alcohol consumption. As an experimental model of ACM, we fed wild‐type and Fgf21 knockout (Fgf21−/−) mice with a 4% alcohol liquid diet for 4 and 12 weeks. FGF21 circulating levels and FGF21 expression in the myocardium were also increased in wild‐type mice after chronic alcohol intake. Fgf21−/− mice develop a higher degree of cardiac hypertrophy, fibrosis, and cardiac dysfunction after chronic alcohol consumption than wild‐type mice. Moreover, the myocardium of Fgf21−/− mice showed signs of metabolic deregulation, oxidative stress, and mitochondrial dysfunction after alcohol intake. Finally, human cardiac biopsies from patients with chronic alcohol consumption developing ACM presented a higher degree of oxidative stress which positively correlated with the FGF21 protein levels in the myocardium. We conclude that plasma levels and cardiac myocyte FGF21 expression were induced in response to chronic alcohol consumption. The lack of FGF21 aggravated cardiac damage produced by ACM, in association with enhanced mitochondrial and oxidative stress, thus pointing to FGF21 as a protective agent against development of alcohol‐induced cardiomyopathy. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

FGF21: a promising therapeutic agent for alcoholic cardiomyopathy?†

“…In line with the suggested role of FGF21 in decreasing cardiac damage, a recent study published in The Journal of Pathology by Ferrer‐Curriu, Guitart‐Mampel et al investigated FGF21 function in ACM [7]. This study analyzed plasma and hearts from healthy donors and patients with chronic alcohol misuse, finding that cardiac and circulating FGF21 levels increased with chronic alcohol intake whether alcoholic cardiomyopathy (ACM) developed or not.…”

“…To investigate FGF21 relevance in ACM, whole‐body FGF21 knockout mice ( Fgf21 KO) received the same alcoholic diet as WT based on a pair‐feeding design. Mice lacking FGF21 were more prone to develop alcohol‐induced cardiac damage with a higher degree of hypertrophy, fibrosis, and impairment in systolic and diastolic function [7].…”

“…In line with the crucial role of FGF21 in lipid metabolism, Ferrer‐Curriu, Guitart‐Mampel et al demonstrated a reduction in levels of the critical fatty acid β oxidation‐related mRNAs peroxisome proliferator‐activated receptor alpha ( Ppara ), very long‐chain acyl‐CoA dehydrogenase ( Acadvl ), and acyl‐CoA oxidase 1 ( Acox1 ) in the hearts of Fgf21 KO mice exposed to chronic alcohol treatment, which might compromise myocardial fatty acid oxidation rate resulting in lipid accumulation. However, cardiac steatosis, assessed by lipid droplet quantification, was not significantly different in alcohol‐treated WT and Fgf21 KO mice [7].…”

“…Importantly, cardiac oxidative stress correlated with FGF21 levels in humans with alcohol cardiomyopathy. Analyses of autophagic markers showed a reduction of LC3 II and an increase of the mitophagy protein Parkin in the hearts of alcoholic‐FGF21‐ablated mice, suggesting an impairment in autophagy/mitophagy pathways [7]. A limitation of this study is that autophagic activity was based on autophagy markers’ static levels without assessing the dynamic nature of autophagic flux by using autophagy inhibitors as recently suggested [9].…”

“…Overall, the present study reinforces the important role that FGF21 plays in cardiac remodeling. Moreover, the finding that FGF21 circulating levels correlate with the degree of cardiac damage in ACM indicates FGF21 as a potential prognostic biomarker for human ACM [7]. However, the study leaves some open issues.…”