https://www.ncbi.nlm.nih.gov/pubmed/30156739 Biliary Atresia

Hepatol Res. 2018 Aug 29. doi: 10.1111/hepr.13245. [Epub ahead of print]
CYP7A1 expression in hepatocytes is retained with upregulated fibroblast growth factor 19 in pediatric biliary atresia.
Hasegawa Y1, Kawai M2, Bessho K1, Yasuda K1, Ueno T3, Satomura Y1, Konishi A1, Kimura T1, Ikeda K1, Tachibana M1, Miyoshi Y1, Michigami T2, Kondou H1,4, Ozono K1.

Abstract

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. FGF19 is then transported via the portal flow, causing transcriptional inhibition of cytochrome P450, family 7, subfamily A, polypeptide 1 (CYP7A1)-a key enzyme in bile acid biosynthesis-via 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 hepatocytes-enriched tissue (HET) despite high serum bile acid concentrations. The FGF19 protein was synthesized in BA HET, and its serum concentration was elevated. FGFR4 was phosphorylated in the BA livers. However, ERK phosphorylation was significantly reduced. We examined the Sprouty homolog 2 (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. FGF19 was increased in BA hepatocytes. By focusing on its regulation in hepatocytes, we demonstrated that the FGF19 pathway did not suppress bile acid synthesis, probably due to an altered mechanism involving upregulated SPRY2 in BA patients.

Published on: 
Aug-2018

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