Author:
Holt Jason A.,Luo Guizhen,Billin Andrew N.,Bisi John,McNeill Y. Yvette,Kozarsky Karen F.,Donahee Mary,Wang Da Yuan,Mansfield Traci A.,Kliewer Steven A.,Goodwin Bryan,Jones Stacey A.
Abstract
The nuclear bile acid receptor FXR has been proposed to play a central role in the feedback repression of the gene encoding cholesterol 7α-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 ofCYP7A1in primary cultures of human hepatocytes and mouse liver through a c-Jun N-terminal kinase (JNK)-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.
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
596 articles.
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