The reduced expression of the
bile salt export pump (BSEP/ABCB11) at the canalicular membrane is associated with
cholestasis-induced hepatotoxicity due to the accumulation of
bile acids in hepatocytes. We previously reported that
4-phenylbutyrate (4PBA), an approved
drug for
urea cycle disorders, is a promising agent for
intrahepatic cholestasis because it increases both the cell surface expression and the transport capacity of BSEP. In the present study, we searched for effective compounds other than 4PBA by focusing on short- and medium-chain
fatty acids, which have similar characteristics to 4PBA such as their low-molecular-weight and a carboxyl group. In transcellular transport studies using Madin-Darby canine kidney (MDCK) II cells, all short- and medium-chain
fatty acids tested except for
formate,
acetate, and
hexanoic acid showed more potent effects on wild type (WT) BSEP-mediated [3H]
taurocholate transport than did 4PBA. The increase in WT BSEP transport with
butyrate and
octanoic acid treatment correlated with an increase in its expression at the cell surface. Two PFIC2-type variants, E297G and D482G BSEP, were similarly affected with both compounds treatment. The prolonged half-life of cell surface-resident WT BSEP was responsible for this increased
octanoic acid-stimulated transport, but not for that of
butyrate. In conclusion, short- and medium-chain
fatty acids have potent effects on the increase in WT and PFIC2-type BSEP-mediated transport in MDCK II cells. Although both short- and medium-chain
fatty acids enhance the transport capacity of WT and PFIC2-type BSEP by inducing those expressions at the cell surface, the underlying mechanism seems to differ between
fatty acids.