Targeting FGF21 in cardiovascular and metabolic diseases: from mechanism to medicine

Abstract

Cardiovascular and metabolic disease (CVMD) is becoming increasingly prevalent in developed and developing countries with high morbidity and mortality. In recent years, fibroblast growth factor 21 (FGF21) has attracted intensive research interest due to its purported role as a potential biomarker and critical player in CVMDs, including atherosclerosis, coronary artery disease, myocardial infarction, hypoxia/reoxygenation injury, heart failure, type 2 diabetes, obesity, and nonalcoholic steatohepatitis. This review summarizes the recent developments in investigating the role of FGF21 in CVMDs and explores the mechanism whereby FGF21 regulates the development of CVMDs. Novel molecular targets and related pathways of FGF21 (adenosine 5'-monophosphate-activated protein kinase, silent information regulator 1, autophagy-related molecules, and gut microbiota-related molecules) are highlighted in this review. Considering the poor pharmacokinetics and biophysical properties of native FGF21, the development of new generations of FGF21-based drugs has tremendous therapeutic potential. Related preclinical and clinical studies are also summarized in this review to foster clinical translation. Thus, our review provides a timely and insightful overview of the physiology, biomarker potential, molecular targets, and therapeutic potential of FGF21 in CVMDs.

Circulating serum fibroblast growth factor 21 as risk and prognostic biomarker of retinal artery occlusion

“…FGF21 through the mediation of the FGFR1/β-Klotho-PI3K-Akt1-BAD signaling network to reduce cell death, and myocardial infarction thereby ameliorating myocardial function 35 . On the other hand, FGF21 can improve glucose homeostasis in a variety of ways, including stimulates insulin expression and secretion via the PI3K/Akt signaling pathway, protect β cells by activating AMPK-acetyl CoA carboxylase (ACC) and PPARδ/γ signaling pathway, and prevent systemic insulin resistance by increasing adiponectin levels 36 . In fundus disease vivo models, FGF21 prevents pathological neovascularization in the retina and choroid 37 , while also playing a protective role in preserving photoreceptor function in diabetic mice 14 .…”

Investigation of FGF21 mRNA levels and relative mitochondrial DNA copy number levels and their relation in nonalcoholic fatty liver disease: a case-control study

“…FGF21 elevation can be seen as another compensatory mechanism in these patients. However, we do not fully understand the molecular regulatory mechanisms behind its function yet ( Watanabe et al, 2020 ; Tan et al, 2023 ). In our study we detected remarkable increase in its expression in liver tissue of NAFLD patients compared to of control group.…”

FGF21 improves ventricular remodeling in TAC induced heart failure rats

“…While preclinical studies have found that FGF21 plays a favorable role in the pathophysiological process of heart failure [3][4][5] . Clinically, this increase in serum FGF21 seems to be contradictory with the results of preclinical studies.…”

“…FGF21 has attracted much attention due to its multiple bene cial effects in regulating glucolipid homeostasis and energy metabolism. The protective effect against damage caused by abnormal metabolic conditions of FGF21 plays a crucial role in cardiovascular and metabolic diseases [3,4] . A recent study illustrated that compared with wild-type mice, FGF21 knockout mice had more obvious myocardial hypertrophy and brosis, increased markers of cardiac injury, hypertrophy and brosis, along with signi cantly decreased ejection fraction, while exogenous administration of FGF21 could improve these pathological changes.…”