Dataset Information

Cytoplasmic tyrosine phosphatase Shp2 coordinates hepatic regulation of bile acid and FGF15/19 signaling to repress bile acid synthesis.

ABSTRACT: Bile acid (BA) biosynthesis is tightly controlled by intrahepatic negative feedback signaling elicited by BA binding to farnesoid X receptor (FXR) and also by enterohepatic communication involving ileal BA reabsorption and FGF15/19 secretion. However, how these pathways are coordinated is poorly understood. We show here that nonreceptor tyrosine phosphatase Shp2 is a critical player that couples and regulates the intrahepatic and enterohepatic signals for repression of BA synthesis. Ablating Shp2 in hepatocytes suppressed signal relay from FGFR4, receptor for FGF15/19, and attenuated BA activation of FXR signaling, resulting in elevation of systemic BA levels and chronic hepatobiliary disorders in mice. Acting immediately downstream of FGFR4, Shp2 associates with FRS2? and promotes the receptor activation and signal relay to several pathways. These results elucidate a molecular mechanism for the control of BA homeostasis by Shp2 through the orchestration of multiple signals in hepatocytes.

SUBMITTER: Li S

PROVIDER: S-EPMC4365973 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cytoplasmic tyrosine phosphatase Shp2 coordinates hepatic regulation of bile acid and FGF15/19 signaling to repress bile acid synthesis.

Li Shuangwei S Hsu Diane D F DD Li Bing B Luo Xiaolin X Alderson Nazilla N Qiao Liping L Ma Lina L Zhu Helen H HH He Zhao Z Suino-Powell Kelly K Ji Kaihong K Li Jiefu J Shao Jianhua J Xu H Eric HE Li Tiangang T Feng Gen-Sheng GS

Cell metabolism 20140626 2

Bile acid (BA) biosynthesis is tightly controlled by intrahepatic negative feedback signaling elicited by BA binding to farnesoid X receptor (FXR) and also by enterohepatic communication involving ileal BA reabsorption and FGF15/19 secretion. However, how these pathways are coordinated is poorly understood. We show here that nonreceptor tyrosine phosphatase Shp2 is a critical player that couples and regulates the intrahepatic and enterohepatic signals for repression of BA synthesis. Ablating Shp ...[more]

PMID: 24981838

Similar Datasets

Project description:Hepatic bile acid synthesis is subject to complex modes of transcriptional control, in which the bile acid-activated nuclear receptor farnesoid X receptor (FXR) in liver and intestine-derived, FXR-controlled fibroblast growth factor 15 (Fgf15) are involved. The Fgf15 pathway is assumed to contribute significantly to control of hepatic bile acid synthesis. However, scientific evidence supporting this assumption is primarily based on gene expression data. Using intestine-selective FXR knockout mice (iFXR-KO), we show that contribution of intestinal FXR-Fgf15 signalling in regulation of hepatic cholesterol 7?-hydroxylase (Cyp7A1) expression depends on time of the day with increased hepatic Cyp7A1 expression in iFXR-KO mice compared with controls exclusively during the dark phase. To assess the physiological relevance hereof, we determined effects of intestine-selective deletion of FXR on physiological parameters such as bile formation and kinetics of the enterohepatic circulation of bile acids. It appeared that intestinal FXR deficiency leads to a modest but significant increase in cholic acid pool size, without changes in fractional turnover rate. As a consequence, bile flow and biliary bile acid secretion rates were increased in iFXR-KO mice compared with controls. Feeding a bile acid-containing diet or treatment with a bile acid sequestrant similarly affected bile formation in iFXR-KO and control mice and induced similar changes in Cyp7A1 and Cyp8B1 expression patterns. In conclusion, this study is the first to demonstrate the physiological relevance of the contribution of the intestinal FXR-Fgf15 signalling pathway in control of hepatic bile acid synthesis. Fgf15 contributes to the regulation of hepatic bile acid synthesis in mice mainly during the dark phase. Expansion of the circulating bile acid pool as well as bile acid sequestration diminishes the contribution of intestinal FXR-Fgf15 signalling in control of hepatic bile acid synthesis and bile formation.

Dataset Information

Cytoplasmic tyrosine phosphatase Shp2 coordinates hepatic regulation of bile acid and FGF15/19 signaling to repress bile acid synthesis.

Publications

Cytoplasmic tyrosine phosphatase Shp2 coordinates hepatic regulation of bile acid and FGF15/19 signaling to repress bile acid synthesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets