Abstract
Bile salt export pump (Bsep) is responsible for the biliary excretion of majority of bile salts in the liver. Dysfunction of Bsep often leads to disruption of the enterohepatic circulation of bile salts and thus cholestasis. Berberine (BBR), an active component of certain traditional herbal medicine such as Goldenseal, shows anti‐oxidative and anti‐inflammatory properties. Nuclear factor erythroid 2‐related factor (Nrf) 2 plays important roles in fighting against oxidative stress and inflammation. We recently showed that BBR increased Bsep mRNA expression in mouse liver. However, the underlying mechanism by which BBR induces Bsep expression remains largely unknown. The present study was designed to determine whether BBR induces Bsep expression via activation of Nrf2 signaling. BBR dose‐dependently increased mRNA and protein expression of Bsep in mouse liver. The studies, conducted in cultured mouse and human hepatoma cells, showed that BBR (1) increased Bsep/BSEP mRNA and protein expression, (2) enhanced the cellular efflux of Dichlorofluorescin diacetate, a known Bsep/BSEP substrate, and (3) stimulated the Bsep/BSEP gene promoter‐driven luciferase reporter activity. To determine whether Nrf2 activity is responsible for BBR‐induced Bsep expression, we knocked down Nrf2 expression in cultured hepatoma cells by using silence RNA (siRNA) that specifically targets Nrf2. Our results showed that after Nrf2 knock‐down, BBR no longer induced BSEP mRNA expression in human hepatoma cells. In contrast, in mouse hepatoma cells, Nrf2 silence partially attenuated BBR‐induced Bsep expression. In addition, promoter partial‐deletion followed by promoter‐driven luciferase reporter assay showed that deletion of putative Nrf2 binding site(s) in mouse and human Bsep/BSEP gene promoter abolished BBR‐induced luciferase activity in human but not mouse hepatoma cells. In conclusion, BBR induces human BSEP expression via Nrf2 signaling. In contrast, BBR induced Bsep expression in mouse liver or hepatoma cells independent of Nrf2 signaling.
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