Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis

被引：556

作者：

Holt, JA

Luo, GZ

Billin, AN

Bisi, J

McNeill, YY

Kozarsky, KF

Donahee, M

Wang, DY

Mansfield, TA

Kliewer, SA

Goodwin, B

Jones, SA ^{[1
]}

机构：

[1] GlaxoSmithKline, Nucl Receptor Discovery Res, Res Triangle Pk, NC 27709 USA

[2] GlaxoSmithKline, High Throughput Biol, Res Triangle Pk, NC 27709 USA

[3] GlaxoSmithKline, Gene Interference, Res Triangle Pk, NC 27709 USA

[4] GlaxoSmithKline, Transgen, Res Triangle Pk, NC 27709 USA

[5] GloxoSmithKline, Prot Agents & Human Gene Therapy, King Of Prussia, PA 19406 USA

[6] GloxoSmithKline, Prot Biochem, King Of Prussia, PA 19406 USA

[7] CuraGen Corp, New Haven, CT 06511 USA

来源：

GENES & DEVELOPMENT | 2003年 / 17卷 / 13期

关键词：

CYP7A1; FXR; bile acid; fibroblast growth factor; JNK;

D O I：

10.1101/gad.1083503

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The nuclear bile acid receptor FXR has been proposed to play a central role in the feedback repression of the gene encoding cholesterol 7alpha-hydroxylase (CYP7A1), the first and rate-limiting step in the biosynthesis of bile acids. We demonstrate that FXR directly regulates expression of fibroblast growth factor-19 (FGF-19), a secreted growth factor that signals through the FGFR4 cell-surface receptor tyrosine kinase. In turn, FGF-19 strongly suppresses expression of CYP7A1 in primary cultures of human hepatocytes and mouse liver through a c-Jun N-terminal kinase (INK)-dependent pathway. This signaling cascade defines a novel mechanism for feedback repression of bile acid biosynthesis and underscores the vital role of FXR in the regulation of multiple pathways of cholesterol catabolism in the liver.

引用

页码：1581 / 1591

页数：11

共 50 条

[1] Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor [J].