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.

Keywords: cardiovascular diseases; fibroblast growth factor 21; metabolic diseases; targets; therapeutics.

Figure 1

Year publications of FGF21 in PubMed (date of search, March 1, 2022). The number of publications on FGF21 is increasing year by year.

Figure 2

FGF21 and cardiovascular and metabolic diseases. Current studies support that FGF21 plays an important role in cardiovascular and metabolic diseases. Nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH).

Figure 3

Molecular functions of FGF21 in cardiovascular and metabolic diseases. (A) The process of hepatic FGF21 production with different activating transcription factors, including peroxisome proliferator-activated receptors (PPARs), activating transcription factor 4 (ATF4), carbohydrate response element-binding protein (ChREBP), and CCR4-NOT transcription complex subunit 6-like (CNOT6 L). (B) FGF21-based drugs that can increase FGF21 levels. (C) FGF21 forms a cell surface receptor complex with FGFR and another coreceptor, β-Klotho (KLB). FGF21 exerts its metabolic protective effects by coordinating target tissues of FGF21, including the brain, liver, adipose tissues, pancreas, cardiac tissue and vasculature, muscles, and intestines. The brain can regulate food preferences and assist in coordinating FGF21-mediated interorgan responses. The liver and adipose tissues are the main targets of FGF21. The direct action of hepatic FGF21 is to regulate lipid and free fatty acid metabolism in the liver. The actions of FGF21 in white adipose tissue (WAT) and brown adipose tissue (BAT) are mainly focused on lipolysis, increasing glucose uptake, and thermogenesis.