Berberine Promotes OATP1B1 Expression and Rosuvastatin Uptake by Inducing Nuclear Translocation of FXR and LXRα

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 mM 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 hLXRa activated OATP1B1 promoter was increased by 2.5-50 mM berberine in a concentration-dependent manner, with halfmaximal effective concentration (EC 50) of 12.19 ± 0.86 and 32.15 ± 2.32 mM, respectively. In addition, after silencing FXR or LXRa by small interfering RNA (siRNA), berberineinduced OATP1B1 expression was significantly attenuated. Western blot analysis of FXR and LXRa 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 LXRa. In conclusion, berberine-induced nuclear translocation of FXR and LXRa could activate OATP1B1 promoter, resulting in enhanced expression of OATP1B1 and increased uptake of rosuvastatin.

Dexamethasone changes the disposition of atorvastatin by targeting the LXRα-OATP1B1 pathway

“…Compared with the control and ATV groups, the protein levels of OATP1B1 were significantly decreased in the DXM and ATV+DXM groups (Figures 4A and B, *P < 0.05, **P < 0.01). Literature suggests that the expression of OATP1B1 can be upregulated when nuclear receptors LXRα are activated [10,14]. Thus, LXRα protein expression was also decreased in DXM and ATV+DXM groups, compared with the control and ATV groups (Figures 4C and D, **P < 0.01, ***P < 0.001).…”

PharmVar GeneFocus: SLCO1B1

“…Likewise, other drugs, endogenous compounds, and natural substances may inhibit the transporter leading to food/herb–drug interactions 52,53 . In addition to inhibition transporter activity, induction effects can occur at the transcriptional level through activation of nuclear receptors 54–56 . Post‐translational regulation of the transporter may also modulate its activity.…”

“…52,53 In addition to inhibition transporter activity, induction effects can occur at the transcriptional level through activation of nuclear receptors. [54][55][56] Post-translational regulation of the transporter may also modulate its activity. For example, chloroquine, an antimalarial drug which is also used to treat autoimmune diseases, was reported to inhibit OATP1B1 degradation by retaining the protein in lysosomes, which leads to decreased OATP1B1-mediated transport of statins, and a higher incidence of SAMSs.…”

Transcriptional Regulation of Solute Carrier Drug Transporters

“…The synthetic FXR agonists GW4064 and fexaramine could significantly increase the transcription activity of SLCO1B1 gene (Meyer Zu Schwabedissen et al, 2010). In addition, berberine could induce the nuclear translocation of FXR and LXRα, which in turn increased the expression of SLCO1B1 (Liu et al, 2020). Both agonists and antagonists of FXR could also regulate the transcription of other SLCO such as SLCO1A2, SLCO1B3-1B7 (LST-3TM12) (Yang et al, 2014;Malagnino et al, 2019).…”