Fibroblast growth factor 7 inhibits cholesterol 7α-hydroxylase gene expression in hepatocytes

• Published in: Biochemical and biophysical research communications 2012-07, Vol.423 (4), p.775-780
• Main Authors: Sun, Zhichao, Yu, Xuemei, Wu, Weibin, Jia, Dongwei, Chen, Yinle, Ji, Lingling, Liu, Xijun, Peng, Xiaomin, Li, Yintao, Yang, Lili, Ruan, Yuanyuan, Gu, Jianxin, Ren, Shifang, Zhang, Songwen
• Format: Article
• Language: English
• Subjects: Animals; Bile Acids and Salts - biosynthesis; Carbon Tetrachloride - toxicity; Cell Line, Tumor; Cholesterol 7-alpha-Hydroxylase - antagonists & inhibitors; Cholesterol 7-alpha-Hydroxylase - genetics; CYP7A1; Disease Models, Animal; FGF7; Fibroblast Growth Factor 7 - pharmacology; Fibroblast Growth Factor 7 - physiology; Gene Expression Regulation, Enzymologic; Hepatic stellate cells; Hepatocytes - drug effects; Hepatocytes - enzymology; Humans; JNK; Liver Cirrhosis - chemically induced; Liver Cirrhosis - enzymology; Liver Cirrhosis - genetics; Male; MAP Kinase Kinase 4 - metabolism; Mice; Mice, Inbred BALB C; Receptor, Fibroblast Growth Factor, Type 2 - genetics; Receptor, Fibroblast Growth Factor, Type 2 - metabolism; RNA, Small Interfering - genetics
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2012.06.035

► FGF7 strongly and rapidly down-regulates the expression of CYP7A1 in hepatocytes. ► FGF7 suppresses the expression of CYP7A1 via FGFR2 and downstream JNK activation. ► Blocking FGF7 abrogates HSC-induced inhibition of CYP7A1 expression in hepatocytes. 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 (CCl4)-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.