Bile acid synthesis in the liver is regulated by the rate-limiting enzyme cholesterol 7␣-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 coactivator 1␣ (PGC-1␣) 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;46:1993-2002.) B ile acids are physiological detergents that facilitate absorption, transport, and distribution of sterols and lipid-soluble vitamins and disposal of toxic metabolites and xenobiotics. Bile acid synthe-sis and cholesterol 7␣-hydroxylase (CYP7A1) 2 gene transcription are inhibited by bile acids returning to the liver via enterohepatic circulation of bile acids. 1
Because bile acids are amphipathic molecules that function as powerful detergents, their concentrations in hepatocytes have to be tightly regulated to prevent cell damage. 2 Bile acids are also signaling molecules that activate nuclear receptors including farnesoid X receptor (FXR), pregnane X receptor, and vitamin D3 receptor and play important roles in the regulation of bile acid synthesis, cholesterol metabolism, and drug metabolism. 2 It has been reported that bile acid synthesis and CYP7A1 activity are suppressed after partial hepatectomy and during liver regeneration in animals and human patients. [3][4][5] The increase of bile acids in the remaining hepatocytes after partial hepatectomy and in the early stage of liver regeneration and injury inhibits bile acid synthesis and increases bile acid excretion to protect the liver from accumulating toxic bile acids. A recent study showed that bile acids and FXR are involved in liver regeneration in mice, as FXR-null mice had a lower rate of liver regeneration. 6 However, the molecular mechanism underlying the bile acid effect on liver regeneration remains unclear.