Fibroblast growth factor 7 inhibits cholesterol 7α-hydroxylase gene 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 (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.
Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China.
Zhichao
Z
Sun
Xuemei
X
Yu
Weibin
W
Wu
Dongwei
D
Jia
Yinle
Y
Chen
Lingling
L
Ji
Xijun
X
Liu
Xiaomin
X
Peng
Yintao
Y
Li
Lili
L
Yang
Yuanyuan
Y
Ruan
Jianxin
J
Gu
Shifang
S
Ren
Songwen
S
Zhang
D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002251:Carbon Tetrachloride / Q000633:toxicity; D045744:Cell Line, Tumor; D002790:Cholesterol 7-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000235:genetics*; D004195:Disease Models, Animal; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D034741:RNA, Small Interfering / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism
D001647:Bile Acids and Salts; D034741:RNA, Small Interfering; D051523:Fibroblast Growth Factor 7; D002251:Carbon Tetrachloride; D002790:Cholesterol 7-alpha-Hydroxylase; D051497:Receptor, Fibroblast Growth Factor, Type 2; D048670:MAP Kinase Kinase 4