Fibroblast growth factor 21 enhances cholesterol efflux in THP-1 macrophage-derived foam cells

Abstract

Abstract. Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator. The present study aimed to investigate the effect of FGF21 on cholesterol efflux and the expression of ATP binding cassette (ABC) A1 and G1 in human THP-1 macrophage-derived foam cells. Furthermore, the present study aimed to investigate the role of the liver X receptor (LXR) α in this process. A model of oxidized low-density lipoprotein-induced foam cells from human THP-1 cells was established. The effect of FGF21 on cholesterol efflux was analyzed using a liquid scintillation counter. The expression of ABCA1 and ABCG1 was determined using quantitative polymerase chain reaction and western blot analyses. FGF21 was found to enhance apolipoprotein A1-and high-density lipoprotein-mediated cholesterol efflux. FGF21 was also observed to increase the mRNA and protein expression of ABCA1 and ABCG1. Furthermore, LXRα-short interfering RNA attenuated the stimulatory effects induced by FGF21. These findings suggest that FGF21 may have a protective effect against atherosclerosis by enhancing cholesterol efflux through the induction of LXRα-dependent ABCA1 and ABCG1 expression. IntroductionAtherosclerosis, one of the leading causes of morbidity and mortality worldwide, is a chronic inflammatory disease and a disorder of lipid metabolism (1). The accumulation of excess cholesterol has been recognized as a crucial event in the development of atherosclerosis (2); therefore, preventing or reversing cholesterol accumulation may be effective protective strategies against atherosclerosis. A growing body of evidence suggests that high density lipoprotein (HDL) has an important role in the removal of cholesterol from atherosclerotic plaques and the transport of the excess cholesterol back to the liver for its subsequent elimination as bile acids and neutral steroids. This process is termed reverse cholesterol transport (RCT) and is one of the major protective mechanisms against the development of atherosclerosis (3-5).Cholesterol efflux from macrophage-derived foam cells is an initial and key step in RCT (6), and serves as an integrated measure of HDL quantity and quality (7). This cholesterol efflux involves numerous genes, including ATP-binding cassette (ABC) A1 and G1 (8). ABCA1 is a member of the ABC superfamily and is the defective gene in Tangier disease. ABCA1 has been reported to have an important role in the prevention of atherosclerosis through facilitating cholesterol efflux from macrophages to lipid-poor apolipoproteinA-Ⅰ (apoA-Ⅰ), and decreasing cholesterol accumulation in macrophages (9). Similar to ABCA1, ABCG1 is capable of promoting cholesterol efflux from macrophages to mature HDL particles, but not to apoA-Ⅰ (10).Liver X receptor (LXR) α, a member of the nuclear hormone receptor superfamily, has a crucial role in cholesterol metabolism (11). Upon activation, LXRα induces numerous genes, which are involved in cholesterol efflux, absorption, transport and excretion. ABCA1 and ABCG1 have been identified as direct targets of LXRα (12).Fibro...

Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia

“…Consistent with this finding, FGF21 was found to enhance ABCA1 and ABCG1 expression and CEC via the liver X receptor a in THP-1-derived foam cells. 55 The enhancement of CEC by pemafibrate treatment may contribute to ASCVD risk reduction because reduced CEC has been associated with the presence of coronary artery disease 5 and CEC was inversely correlated with cardiovascular event risk. 6 With regard to TRLs, the patients presented very high peaks of postprandial TG and RemL-C levels at baseline, suggesting that they were at high ASCVD risk.…”

Apolipoprotein E deficiency and high-fat diet cooperate to trigger lipidosis and inflammation in the lung via the toll-like receptor 4 pathway

“…Adenosine triphosphatase-binding cassette transporter A1 (ABCA1) mediates the efflux of cholesterol to lipid-poor apolipoproteins (ApoA1 and ApoE) (20). It was reported that ABCA1 −/− mice displayed lung cholesterol accumulation and inflammation (21).…”

Heat Shock Gene Sirtuin 1 Regulates Post-Prandial Lipid Metabolism with Relevance to Nutrition and Appetite Regulation in Diabetes

“…Food restriction and fasting regulate Sirt 1 and FGF21 involved in the prevention of the metabolic syndrome and maintenance of high density lipoprotein levels [39][40][41]. FGF21 therapy [42,43] in Type 2 and Type 3 diabetes may be ineffective with the development of cardiac ageing with relevance to core body temperature regulation that is determined by mi-34a/Sirt 1 gene expression with low adiponectin levels [36,44] (Figure 2).…”