Yuan Le

Date of Award


Document Type


Degree Name

Philosophy (Ph.D)


Pharmaceutical Sciences

First Advisor

Xingguo Cheng

Second Advisor

Louis Trombetta

Third Advisor

Sue Ford


Bile salt export pump (Bsep) is primarily responsible for biliary excretion of bile salts in the liver. Genetic mutation or drug-induced dysfunction of Bsep often leads to disruption of enterohepatic circulation of bile acids and consequently cholestatic liver injury. Berberine (BBR), a traditional herbal medicine, promotes bile flow and has been suggested to treat liver diseases, including cholestasis. We recently reported that BBR induces Bsep expression in mouse liver. However, the underlying mechanism by which BBR induces Bsep expression is unknown. My dissertation project showed that BBR induced mouse and human Bsep/BSEP mRNA and protein expression. In addition, BBR increased Bsep/BSEP transport activity, evidenced by increased cellular efflux of dichlorofluorescin diacetate, a selective Bsep substrate. BBR activated NRF2 signaling in human hepatoma cells, which contributed to BBR-induced human BSEP expression. However, activation of Nrf2 signaling was not essential for induction of mouse Bsep by BBR because BBR continued to increase Bsep expression in Nrf2-null mouse liver and Nrf2-silenced mouse hepatoma cells. In addition, BBR reversed LPS-decreased mouse Bsep expression in both mouse liver and cultured mouse hepatoma cells. Mechanistically, BBR attenuated LPS-activated TLR4-NF-кB signaling, which may contribute to BBR-induced mouse Bsep expression. In conclusion, BBR induced human BSEP expression through NRF2 activation; whereas BBR induced mouse Bsep expression most likely through TLR4 inhibition.