Cholestasis is a common condition in which the flow of bile from the liver to the intestines is inhibited. It has been shown that organic
anion-transporting
polypeptide 3A1 (OATP3A1) is upregulated in
cholestasis to promote
bile acid efflux transport. We have previously shown that the
growth factor fibroblast growth factor 19 and inflammatory mediator
tumor necrosis factor α (TNFα) increased OATP3A1
mRNA levels in
hepatoma peritoneal lavage cell/PRF/5 cell lines. However, the mechanism underlying TNFα-stimulated OATP3A1 expression in
cholestasis is unknown. To address this, we collected plasma samples from control and obstructive
cholestasis patients and used ELISA to detect TNFα levels. We found that the TNFα levels of plasma and hepatic
mRNA transcripts were significantly increased in obstructive cholestatic patients relative to control patients. A significant positive correlation was also observed between plasma TNFα and liver OATP3A1
mRNA transcripts in patients with obstructive
cholestasis. Further mechanism analysis revealed that recombinant TNFα induced OATP3A1 expression and activated NF-κB and
extracellular signal-regulated kinase (ERK) signaling pathways as well as expression of related
transcription factors p65 and specificity
protein 1 (SP1). Dual-
luciferase reporter and
chromatin immunoprecipitation assays showed that recombinant TNFα upregulated the binding activities of NF-κB p65 and SP1 to the OATP3A1 promoter in peritoneal lavage cell/PRF/5 cells. These effects were diminished following the application of NF-κB and ERK inhibitors
BAY11-7082 and
PD98059. We conclude that TNFα stimulates hepatic OATP3A1 expression in human obstructive
cholestasis by activating NF-κB p65 and ERK-SP1 signaling. These results suggest that TNFα-activated NF-κB p65 and ERK-SP1 signaling may be a potential target to ameliorate
cholestasis-associated liver injury.