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Numbers animal- and clinical-based studies demonstrate that fibrates, an agonist of peroxisome proliferator-activated receptors, are widely used in clinics for its beneficial effect of anti-hyperlipidemia and cardiovascular disease. However, its exact mechanism required further investigated.
This study evaluated the impact of fibroblast growth factor (FGF21) deficiency on the protective effect of fenofibrate against atherosclerosis in mice after treatment with fenofibrate, and explored its potential molecular of FGF21 to mediate the beneficial effect of fibrate to reverse dyslipidemia and prevent the development of atherosclerosis in mice.
Apolipoprotein E(apoE) and apoE/FGF21 double knockout (DKO) mice were administrated by fenofibrate (100mg/kg.day) for 8 weeks to test the impact of FGF21 in the protective effect of fenofibrate against atherosclerosis. The potential molecular mechanism of FGF21 mediates the protective effect of fenofibrates against atherosclerosis were also explored in primary cultured hepatocytes.
Treatment with fenofibrate significantly prevents aortic atherosclerotic plaque formation in both apoE KO and DKO mice, which is accompanied by decreasing hyperlipidemia as well as systemic and local inflammation. However, these protective effects of fenofibrates were markedly weakened in FGF21 deficient mice. Mechanistically, treatment with fenofibrate strongly increased hepatic FGF21 expression and inhibited the expression levels of hepatic sterol regulatory element-binding protein 2 (Srebp-2) in apolipoprotein E (apoE) KO mice, therefore leading to reduce cholesterol synthesis and attenuation of hypercholesterolemia in mice. On the other hand, fenofibrates also prominently elevated serum and hepatic PON1 protein levels and its bioactivities, which in turn acts on the blood vessels to inhibit local ROS and inflammation. In primary cultured human umbilical vein endothelial cells, fenofibrate induced PON1 expression by activation of FGF21-AMPK axis, consequently leading to inhibition of ROS production and inflammation caused by ox-LDL.
Our findings suggest that fenofibrate-induced production of FGF21 serves as an adaptive mechanism to ameliorate atherosclerosis by suppression of Srebp-2-dependent cholesterol synthesis and promoting PON1-mediated clearance of blood vessel ROS and inflammation.