RESUMEN

Cholesterol 7α-hydroxylase (CYP7A1) is the initial and rate-limiting enzyme for bile acid synthesis. Transcription of the CYP7A1 gene is regulated by bile acids, nuclear receptors and cytokines. Fibroblast growth factor 7 (FGF7) secreted from activated hepatic stellate cells (HSC) during chronic liver fibrosis regulates hepatocyte survival and liver regeneration. In the carbon tetrachloride (CCl(4))-induced fibrotic mouse liver, we demonstrated that the expression of CYP7A1 was largely decreased while the expression of FGF7 was significantly increased. We further demonstrated that FGF7 inhibited CYP7A1 gene expression in hepatocytes. Knockdown study by short interfering RNA, kinase inhibition and phosphorylation assays revealed that the suppression of CYP7A1 expression by FGF7 was mediated by FGFR2 and its downstream JNK signaling cascade. The FGF7 neutralizing antibody restored CYP7A1 expression in Hep3B cells treated with conditioned medium from HSC. In summary, the data suggest that FGF7 is a novel regulator of CYP7A1 expression in hepatocytes and may prevent hepatocytes from accumulating toxic bile acids during liver injury and fibrosis.

Asunto(s)

Ácidos y Sales Biliares/biosíntesis , Colesterol 7-alfa-Hidroxilasa/genética , Factor 7 de Crecimiento de Fibroblastos/fisiología , Regulación Enzimológica de la Expresión Génica , Hepatocitos/enzimología , Cirrosis Hepática/enzimología , Animales , Tetracloruro de Carbono/toxicidad , Línea Celular Tumoral , Colesterol 7-alfa-Hidroxilasa/antagonistas & inhibidores , Modelos Animales de Enfermedad , Factor 7 de Crecimiento de Fibroblastos/farmacología , Hepatocitos/efectos de los fármacos , Humanos , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/genética , MAP Quinasa Quinasa 4/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , ARN Interferente Pequeño/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo