The Role of Fibroblast Growth Factor 21 in Diabetic Cardiovascular Complications and Related Epigenetic Mechanisms

Abstract

Fibroblast growth factor 21 (FGF21), is an emerging metabolic regulator mediates multiple beneficial effects in the treatment of metabolic disorders and related complications. Recent studies showed that FGF21 acts as an important inhibitor in the onset and progression of cardiovascular complications of diabetes mellitus (DM). Furthermore, evidences discussed so far demonstrate that epigenetic modifications exert a crucial role in the initiation and development of DM-related cardiovascular complications. Thus, epigenetic modifications may involve in the function of FGF21 on DM-induced cardiovascular complications. Therefore, this review mainly interprets and delineates the recent advances of role of FGF21 in DM cardiovascular complications. Then, the possible changes of epigenetics related to the role of FGF21 on DM-induced cardiovascular complications are discussed. Thus, this article not only implies deeper understanding of the pathological mechanism of DM-related cardiovascular complications, but also provides the possible novel therapeutic strategy for DM-induced cardiovascular complications by targeting FGF21 and related epigenetic mechanism.

Keywords: FGF21; cardiovascular complications; diabetes; epigenetic; mechanisms.

Figure 1

The mechanisms of exogenous FGF21 action in DCM treatment. FGF21 plays an anti-apoptosis role in cardiomyocytes by activating PI3K/Akt2/Bcl-2/Bax/Caspase 3 pathway and ERK1/2/p38 MAPK/AMPK pathway. FGF21 protects against oxidative stress by activating AMPK/Akt2/GSK3β/Fyn/Nrf2 pathway. FGF21 lowers lipid accumulation via activating AMPK/ACC/CPT-1 pathway and ERK1/2/PGC-1α/CPT-1 pathway in the myocardium. FGF21 reduces inflammation in cardiomyocytes by upregulating AMPK/PON1 signaling. The effect of FGF21 on the treatment of DCM is also regulated by adiponectin. PI3K, phosphatidylinositol-3-kinase; Akt2, protein kinase B; Bcl-2, B-cell lymphoma-2; Bax, Bcl-2-associated X protein; ERK1/2, extracellular signal-regulated kinase 1/2; p38 MAPK, mitogen-activated protein kinase 14; AMPK, adenosine 5′-monophosphate (AMP)-activated protein kinase; GSK3β, glycogen synthase kinase-3β; Nrf2, nuclear factor (erythroid-derived 2)-like 2; ACC, acetyl-CoA carboxylase; CPT-1, carnitine palmitoyltransferase 1; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α; PON1, paraoxonase 1; DCM, diabetic cardiomyopathy.

Figure 2

Possible epigenetic modifications targeting FGF21 in diseases related to DM. HDAC3 inhibition by GRFP966 promotes Nrf2 activity via the up-regulation of miRNA-200a expression with down-regulation of keap1 to preserve expression of hepatic FGF21 in diabetic aorta injury model. In high fat diet-induced obesity model, down-regulation of miRNA-34a improves hepatic expression of FGF21 signaling and SIRT1 to promote browning fat formation. Expression of FGF21 is reduced by Dnmt3a-mediated DNA methylation at the Fgf21 promoter. NaB increases Fgf21 gene transcription by inhibiting HDAC3 interacts with PPARα in the Fgf21 promoter. HDAC3, histone deacetylase 3; miRNA-200a, microRNA-200a; Keap1, kelch-like ECH-associated protein 1; Nrf2, Nuclear factor (erythroid-derived 2)-like 2; ARE, AU-rich element; FGFR, fibroblast growth factor receptor; β-KL, β-klotho; miRNA-34a, microRNA-34a; SIRT1, sirtuin 1; PGC1α, peroxisome proliferator-activated receptorγcoactivator-1 α; Ucp1, uncoupled protein 1; Prdm16, PRD1-BF1 and RIZ1 homeodomain protein 16; Dnmt3a, DNA methyltransferase 3a; NaB, sodium butyrate; PPARα, peroxisome proliferator activate receptor α.