Cytoplasmic Tyrosine Phosphatase Shp2 Coordinates Hepatic Regulation of Bile Acid and FGF15/19 Signaling to Repress Bile Acid Synthesis

• Published in: Cell metabolism Vol. 20; no. 2; pp. 320 - 332
• Main Authors: Li, Shuangwei, Hsu, Diane D.F., Li, Bing, Luo, Xiaolin, Alderson, Nazilla, Qiao, Liping, Ma, Lina, Zhu, Helen H., He, Zhao, Suino-Powell, Kelly, Ji, Kaihong, Li, Jiefu, Shao, Jianhua, Xu, H. Eric, Li, Tiangang, Feng, Gen-Sheng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.08.2014
• Subjects: Animals; Bile Acids and Salts - biosynthesis; Bile Ducts - injuries; Cell Line; Cholesterol 7-alpha-Hydroxylase - metabolism; Fibroblast Growth Factors - metabolism; Liver - metabolism; Liver - pathology; Membrane Proteins - metabolism; Mice; Mice, Knockout; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - deficiency; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Receptor, Fibroblast Growth Factor, Type 4 - metabolism; Signal Transduction; Up-Regulation
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2014.05.020

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 FRS2α 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. [Display omitted] •Shp2/Ptpn11 is required to repress bile acid (BA) biosynthesis in hepatocytes•Shp2 coordinates hepatic responses to BA and FGF15/19 signals•FGFR4 activation by FGF15/19 requires Shp2 activity•Hepatic Shp2 is essential to maintain systemic BA and hepatobiliary homeostasis Li et al. show that the nonreceptor tyrosine phosphatase Shp2 is a critical player that couples and regulates multiple regulatory branches of bile acid (BA) synthesis. Ablating Shp2 in hepatocytes suppressed signal relay from FGFR4, receptor for FGF15/19, and attenuated BA activation of FXR signaling.