FGF21 Increases Cholesterol Efflux by Upregulating ABCA1 Through the ERK1/2–PPARγ–LXRα Pathway in THP1 Macrophage-Derived Foam Cells

Abstract

FGF21, a member of the fibroblast growth factor superfamily, is an important endogenous regulator of systemic glucose and lipid metabolism. Elevated serum FGF21 levels have been reported in subjects with coronary heart disease and carotid artery plaques. However, whether FGF21 is associated with atherosclerotic diseases remains unclear. In this study, the effects of FGF21 on cholesterol efflux in THP1 macrophage-derived foam cells and the underlying mechanisms were investigated. THP1 macrophage-derived foam cells were incubated with 0, 25, 50, 100, 200, and 400 ng/mL of FGF21 for varying time periods (0, 6, 12, and 24 h). Cholesterol efflux onto apoA-1 was assessed by high-performance liquid chromatography assays, while change in ABCA1 expression was analyzed by western blot and real-time quantitative PCR. Incubation was performed with the ERK1/2-specific inhibitor PD98059, PPARγ-specific inhibitor GW9662, and LXRα siRNA. Our results show that FGF21 promotes cholesterol efflux and ABCA1 expression in THP1 macrophage-derived foam cells in a dose- and time-dependent manner. In addition, inhibition of ERK1/2 or PPARγ, or knockdown of LXRα attenuated FGF21-mediated promotion of ABCA1 expression and cholesterol efflux. These results demonstrate that FGF21 can promote cholesterol efflux by upregulating ABCA1 through the ERK1/2-PPARγ-LXRα pathway in THP1 macrophage-derived foam cells.

The relationship of fibroblast growth factor 21 with cardiovascular outcome events in the Fenofibrate Intervention and Event Lowering in Diabetes study

“…It is interesting that the association of FGF21 with total CVD events tended to be stronger in patients with higher total cholesterol. In fact, recent studies have suggested that FGF21 may play a role in cholesterol metabolism [37][38][39].…”

FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs

“…In addition, FGF21 treatment improved aggravated lipid profiles in atherosclerotic rats through its antioxidant effects (Zhu et al 2014). The enhancement of cellular cholesterol efflux from macrophage-derived foam cells by FGF21 may also contribute to the improvement of atherosclerosis (Lin et al 2014). Taken together, these findings suggest that FGF21 plays an adaptive and protective role in response to atherogenic stress, although further studies are needed to validate these findings.…”

Curcumin mediates reversion of HGF-induced epithelial-mesenchymal transition via inhibition of c-Met expression in DU145 cells

“…PCR was performed under the following conditions: Denaturation at 50˚C for 2 min, followed by 38 cycles of 95˚C for 15 sec and 60˚C for 1 min. Gene expression was normalized to internal controls and fold changes were calculated using relative quantification (2 -ΔΔCt ) (12).…”

“…P0012A; Beyotime Institute of Biotechnology) and subsequently transferred to a polyvinylidene difluoride membrane (cat no. FFP39; Beyotime Institute of Biotechnology) (12). The membrane was immunoblotted with anti-β-actin (1:1,000), anti-c-Met (1:500), anti-ERK1/2 (1:250), anti-p-ERK1/2 (1:250), anti-AKT (1:400), anti-p-AKT (1:200), anti-Snai1 (1:400), anti-E-cadherin (1:500) and anti-vimentin (1:500) at 4˚C overnight.…”

“…662102; Greiner Bio-One), and incubated overnight at 37˚C in an atmosphere of 5% CO 2 . DU145 cells were pretreated with 15 µmol/l curcumin for 2 h. HGF was added to each well at a final concentration of 33 ng/ml (12). Cells were subsequently incubated at 37˚C for 48 h. Representative images were captured at magnification, x20 using Eclipse TE2000-U inverted microscope (Nikon, Corporation, Tokyo, Japan).…”