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CYP7A1 expression in hepatocytes is retained with upregulated fibroblast growth factor 19 in pediatric biliary atresia
Author(s) -
Hasegawa Yasuhiro,
Kawai Masanobu,
Bessho Kazuhiko,
Yasuda Kie,
Ueno Takehisa,
Satomura Yoshinori,
Konishi Akiko,
Kimura Takeshi,
Ikeda Kayo,
Tachibana Makiko,
Miyoshi Yoko,
Michigami Toshimi,
Kondou Hiroki,
Ozono Keiichi
Publication year - 2019
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/hepr.13245
Subject(s) - cholesterol 7 alpha hydroxylase , fgf19 , g protein coupled bile acid receptor , bile acid , farnesoid x receptor , fibroblast growth factor , endocrinology , mapk/erk pathway , medicine , signal transduction , biology , cholestasis , receptor , microbiology and biotechnology , biochemistry , transcription factor , nuclear receptor , gene
Aim Bile acid biosynthesis is strictly regulated under physiological conditions. The expression of fibroblast growth factor (FGF) 19 is induced when bile acids bind to the farnesoid X receptor in the intestinal epithelium. Fibroblast growth factor 19 is then transported by the portal flow, causing transcriptional inhibition of cytochrome P450, family 7, subfamily A, polypeptide 1 (CYP7A1), a key enzyme in bile acid biosynthesis, through the extracellular signal‐regulated kinase (ERK) pathway. However, the regulatory mechanisms of these signaling pathways in hepatocytes under chronic cholestasis remain unclear. We investigated the regulation of these signaling pathways in patients with biliary atresia (BA). Methods We analyzed the regulation of molecules in these signaling pathways using liver and serum samples from eight BA children and four non‐cholestatic disease controls. Results CYP7A1 mRNA expression was not inhibited in BA microdissected hepatocyte‐enriched tissue (HET) despite high serum bile acid concentrations. The FGF19 protein was synthesized in BA HET, and its serum concentration was elevated. Fibroblast growth factor receptor 4 was phosphorylated in BA livers. However, ERK phosphorylation was significantly reduced. We examined SPRY2 expression to determine how the ERK pathway was inactivated downstream of the FGF receptor; the expression was significantly increased in BA HET. Conclusions This is the first study to measure the CYP7A1 mRNA levels in human BA HET. Fibroblast growth factor 19 was increased in BA hepatocytes. By focusing on its regulation in hepatocytes, we showed that the FGF19 pathway did not suppress bile acid synthesis, probably due to an altered mechanism involving upregulated SPRY2 in BA patients.