Abstract
Berberine, a quinoline alkaloid, can be used in combination with statins to enhance hypolipidemic effects and reduce the dose and side effects of statins. The hypolipidemic effects of statins in the liver are mainly regulated by organic anion transporting polypeptides (OATPs), and the expression of OATPs is regulated by nuclear receptors. Berberine has been reported to affect nuclear receptors. However, whether berberine affects the uptake of statins by regulating nuclear receptor-mediated expression of OATPs remains to be determined. The aim of this study was to investigate the effects of berberine on the expression of OATP1B1 in HepG2 and explore the underlying mechanism. In HepG2 cells, 10–50 μM berberine significantly increased the uptake of rosuvastatin by inducing the expression of OATP1B1 mRNA and protein. Dual-Luciferase reporter assay showed that luciferase activity of hFXR and hLXRα activated OATP1B1 promoter was increased by 2.5–50 μM berberine in a concentration-dependent manner, with half-maximal effective concentration (EC50) of 12.19 ± 0.86 and 32.15 ± 2.32 μM, respectively. In addition, after silencing FXR or LXRα by small interfering RNA (siRNA), berberine-induced OATP1B1 expression was significantly attenuated. Western blot analysis of FXR and LXRα protein levels in the cytoplasm and nucleus of HepG2 cells after treatment with berberine showed that berberine induced nuclear translocation and activation of FXR and LXRα. In conclusion, berberine-induced nuclear translocation of FXR and LXRα could activate OATP1B1 promoter, resulting in enhanced expression of OATP1B1 and increased uptake of rosuvastatin.
Highlights
Statins have been widely used as lipid-lowering drugs because they are inhibitors for hydroxyl methylglutaryl coenzyme A (HMG-CoA) reductase
To investigate the effects of berberine on the expression of OATP1B1, HepG2 cells were treated with a series of concentrations of berberine (5, 10, 25, and 50 mM) for h, or treated with mM berberine for a series of time (6, 12, 24, and 48 h)
We provide the first evidence that berberine enhanced farnesoid X receptor (FXR) and liver X receptor a (LXRa) mediated upregulation of OATP1B1 expression, resulting in enhanced uptake of the substrate rosuvastatin in HepG2 cells, which may be responsible for improved lipid-lowering efficacy in combination with statins
Summary
Statins have been widely used as lipid-lowering drugs because they are inhibitors for hydroxyl methylglutaryl coenzyme A (HMG-CoA) reductase. The combination therapy of statins with bile acid sequestrants, niacin, or ezetimibine have significantly improved efficacy in the treatment of hyperlipidemia Pregnane X receptor (PXR), constitutive androgen receptor (CAR), farnesoid X receptor (FXR), and liver X receptor a (LXRa) are members of constitutive and ligand-activated nuclear receptor superfamily and play a crucial role in regulating target genes involved in drug metabolism and transport (Urquhart et al, 2007; Staudinger et al, 2013). Rifampicin significantly increases the expression of OATP1B1 protein and mRNA in hepatocytes by activating PXR (Jigorel et al, 2006)
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