Effect of Fibroblast Growth Factor 21 on the Development of Atheromatous Plaque and Lipid Metabolic Profiles in an Atherosclerosis-Prone Mouse Model

Abstract

Fibroblast growth factor 21 (FGF21) is a hormonal regulator of lipid and glucose metabolism. We aimed to investigate the effect of an FGF21 analogue (LY2405319) on the development of atherosclerosis and its associated parameters. ApoE−/− mice were fed an atherogenic diet for 14 weeks and were randomly assigned to control (saline) or FGF21 (0.1 mg/kg) treatment group (n = 10/group) for 5 weeks. Plaque size in the aortic arch/valve areas and cardiovascular risk markers were evaluated in blood and tissues. The effects of FGF21 on various atherogenesis-related pathways were also assessed. Atherosclerotic plaque areas in the aortic arch/valve were significantly smaller in the FGF21 group than in controls after treatment. FGF21 significantly decreased body weight and glucose concentrations, and increased circulating adiponectin levels. FGF21 treatment alleviated insulin resistance and decreased circulating concentrations of triglycerides, which were significantly correlated with plaque size. FGF21 treatment reduced lipid droplets in the liver and decreased fat cell size and inflammatory cell infiltration in the abdominal visceral fat compared with the control group. The monocyte chemoattractant protein-1 levels were decreased and β-hydroxybutyrate levels were increased by FGF21 treatment. Uncoupling protein 1 expression in subcutaneous fat was greater and fat cell size in brown fat was smaller in the FGF21 group compared with controls. Administration of FGF21 showed anti-atherosclerotic effects in atherosclerosis-prone mice and exerted beneficial effects on critical atherosclerosis pathways. Improvements in inflammation and insulin resistance seem to be mechanisms involved in the mitigation of atherosclerosis by FGF21 therapy.

New developments in the biology of fibroblast growth factors

“…In patients with type 2 diabetes (T2D), serum FGF15/19 levels are independently and inversely associated with arteriosclerosis parameters, supporting a protective role for serum FGF15/19 in atherosclerosis progression (W. S. Liu, Tang, et al, 2020). FGF21 also mitigates atherosclerosis in HFD‐fed ApoE −/− mice (Maeng et al, 2020). FGF21 also reduced Fas‐mediated apoptosis induced by oxidized LDL in HUVECs and in ApoE −/− mice (Yan et al, 2018).…”

Fibroblast Growth Factor 21 Predicts Short-Term Prognosis in Patients With Acute Heart Failure: A Prospective Cohort Study

“…Shen et al showed that higher baseline serum FGF21 is associated with CVD mortality in elderly patients during the 5-year follow-up ( 12 ). In addition, the circulating level of FGF21 is also related to the development and prognosis of hypertension and atherosclerosis ( 13 ). Experimental studies show that FGF21 activating MAPK signaling through binding to FGFR1c and its co-receptorβ- Klotho to prevent myocardial hypertrophy ( 14 ).…”

The role of FGF21 in the pathogenesis of cardiovascular disease

“…Several studies have reported the relationship between FGF21 and CVDs, such as CHD, [ 26 ] CMP, [ 27 ] and HF. [ 28 ] FGF21 exerts cardioprotective effects partly by regulating oxidative stress, [ 29 ] lipid metabolism, [ 30 ] autophagy, [ 31 ] and apoptosis [ 32 ] and may be a new target for the prediction and treatment of CVDs. In this study, we attempted to shed light on the recent progress in understanding the relationship between FGF21 and CVDs [Figure 1 ].…”