Hepatic Fgf21 Expression Is Repressed after Simvastatin Treatment in Mice

Abstract

Fibroblast growth factor 21 (Fgf21) is a hormone with emerging beneficial roles in glucose and lipid homeostasis. The interest in Fgf21 as a potential antidiabetic drug and the factors that regulate its production and secretion is growing. Statins are the most widely prescribed drug for the treatment of dyslipidemia. However, the function of statins is not limited to the lowering of cholesterol as they are associated with pleiotropic actions such as antioxidant, anti-inflammatory and cytoprotective effects. The recently described effect of statins on mitochondrial function and the induction of Fgf21 by mitochondrial stress prompted us to investigate the effect of statin treatment on Fgf21 expression in the liver. To this end, C57BL6J male mice and primary mouse hepatocytes were treated with simvastatin, and Fgf21 expression was subsequently assessed by immunoblotting and quantitative real-time PCR. Hepatic Fgf21 protein and mRNA and circulating levels of FGF21significantly decreased in mice that had received simvastatin in their food (0.1% w/w) for 1 week. This effect was also observed with simvastatin doses as low as 0.01% w/w for 1 week or following 2 intraperitoneal injections within a single day. The reduction in Fgf21 mRNA levels was further verified in primary mouse hepatocytes, indicating that the effect of simvastatin is cell autonomous. In conclusion, simvastatin treatment reduced the circulating and hepatic Fgf21 levels and this effect warrants further investigation with reference to its role in metabolism.

High plasma FGF21 levels predicts major cardiovascular events in patients treated with atorvastatin (from the Treating to New Targets [TNT] Study)

“…A recent meta-analysis of controlled clinical trials has shown reduction of plasma free fatty acids (FFAs) by atorvastatin [33], and FFAs can stimulate FGF21 expression in vitro [34]. Short-term simvastatin suppresses hepatic FGF21 expression and reduces circulating FGF21 levels in mice as well as FGF21 expression in mouse primary hepatocytes [10]. All these findings are consistent with our clinical study results.…”

“…However, it is unknown whether circulating FGF21 levels can predict CVD events in statin-treated patients. This is particularly important given that statins are widely used for CVD prevention, and hepatic FGF21 expression is repressed in statin-treated mice [10].…”

Association of elevated circulating fibroblast growth factor 21 levels with prevalent and incident metabolic syndrome: The Multi-Ethnic Study of Atherosclerosis

“…p for interaction was estimated by including the interaction term in the regression models in the full sample after adjustment for the main effects of the covariates. Moreover, as FGF21 levels have been reported to be affected by lipid-lowering medications [10,20] and lipid-lowering medication also affect triglycerides and HDL-C, we excluded participants on lipid-lowering medications at baseline in a sensitivity analysis. A two-tailed p < 0.05 was considered statistically significant.…”

Lentivirus-MediatedhFGF21Stable Expression in Liver of Diabetic Rats Model and Its Antidiabetic Effect Observation

“…10 FGF21 specifically regulates glucose uptake in adipocytes, improves insulin resistance, protects islet beta cells, lowers blood lipid levels, and reduces other lipid metabolism functions in diabetes, indicating that it has great potential as a clinical treatment for metabolic syndromes, such as diabetes, obesity, atherosclerosis, and hepatic adipose infiltration, among other conditions. [11][12][13][14][15][16][17] FGF21 protein is expressed at high levels in the liver, particularly in the fasted state, and causes a series of glycolipid metabolic reactions. [18][19][20][21] In addition, FGF21 is the only FGF member that has not been shown to promote mitosis, which may reduce the risk of side effects in clinical treatments.…”