Hepatocyte growth factor signaling pathway inhibits cholesterol 7α-hydroxylase and bile acid synthesis in human hepatocytes

Bile acid synthesis in the liver is regulated by the rate-limiting enzyme cholesterol 7α-hydroxylase (CYP7A1). Transcription of the CYP7A1 gene is inhibited by bile acids and cytokines. The rate of bile acid synthesis is reduced immediately after partial hepatectomy and during the early stage of liver regeneration. Hepatocyte growth factor (HGF) released from stellate cells activates a receptor tyrosine kinase c-Met, in hepatocytes and stimulates signaling pathways that regulate cell growth, proliferation, and apoptosis. This study demonstrated that HGF strongly and rapidly repressed CYP7A1 mRNA expression and the rate of bile acid synthesis in primary human hepatocytes. HGF rapidly induced c-Jun and small heterodimer partner mRNA and protein expression and increased phosphorylation of ERK1/2, JNK, and c-Jun. Specific inhibitors of protein kinase C, extracellular signal–regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK) blocked HGF inhibition of CYP7A1 expression. Knockdown of c-Met by small interfering RNA resulted in a significant increase in CYP7A1 and blocked HGF inhibition of CYP7A1 mRNA expression. Chromatin immunoprecipitation assays showed that HGF induced recruitment of c-Jun and small heterodimer partner (SHP) but reduced recruitment of the coactivators peroxisome proliferators activated receptor ρ coactivator 1α (PGC-1α) and cAMP response element binding protein (CREB)–binding protein (CBP) to chromatin. Conclusion: This study demonstrated that HGF is a novel regulator of CYP7A1 and bile acid synthesis in human hepatocytes and may protect hepatocytes from accumulating toxic bile acids and developing intrahepatic cholestasis during the early stage of liver regeneration. (Hepatology 2007.)