Hepatocyte growth factor (HGF) ameliorates liver
injuries in hepatectomized cholestatic rats. On the other hand, the
protein level of organic
anion-transporting
polypeptide (Oatp1), which is responsible for the uptake of
bile salts into hepatocytes, decreases in cholestatic humans and rats. However, the relationship between the ameliorative effects of HGF and the decrease in Oatp1 levels in
cholestasis remains to be understood. Therefore, in order to investigate this relationship, we evaluated the effects of HGF on the function and
protein level of Oatp1. HGF treatment significantly increased the uptake of radiolabeled
estradiol 17beta-d-glucuronide ([(3)H]E(2)17betaG), a predominant Oatp1 substrate, in primary cultured rat hepatocytes. Additionally, there was an increase in the Oatp1
protein levels. The increased [(3)H]E(2)17betaG uptake was significantly inhibited by simultaneous incubation with the
HGF receptor antibody and treatment with non-radiolabeled E(2)17betaG. However, inhibition by
taurocholic acid, a Na(+)-
taurocholate co-transporting
polypeptide (Ntcp) substrate, was weaker than that caused by non-radiolabeled E(2)17betaG. Further, the increase was not altered by replacing Na(+) in the medium with Li(+). In the inhibition study, the increased [(3)H]E(2)17betaG uptake was inhibited by Oatp1 substrates, including
bromosulfophthalein,
ochratoxin A, and
ouabain, but not by
digoxin, which is an Oatp2-specific substrate. Furthermore, HGF did not alter the Oatp1
mRNA expression. In contrast, HGF treatment suppressed the ubiquitination of Oatp1
protein. In conclusion, this is the first report suggesting that HGF regulates Oatp1
protein level and that the ameliorative effects of HGF in
cholestasis was induced, at least in part, by correcting the down-regulation of the Oatp1
protein level.