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

Abstract

Summary 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 non-receptor 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 orchestration of multiple signals in hepatocytes.

Preventive Inhibition of Liver Tumorigenesis by Systemic Activation of Innate Immune Functions

“…In subsequent experiments, we focused on Shp2 Δ H mice, as pIC injection induced the strongest tumor-inhibitory effect without affecting gene deletion mediated by Alb-cre in this mouse line. Further, the Shp2 Δ H mutant mice developed hepatic inflammation, cholestasis and fibrosis, mimicking pathogenic processes in human patients with chronic liver diseases predisposed to tumorigenesis (Bard-Chapeau et al, 2011; Li et al, 2014). …”

The effect of fibroblast growth factor 15 deficiency on the development of high fat diet induced non-alcoholic steatohepatitis

“…The role of FGF15 in maintaining bile acid homeostasis has been previously described (Li et al, 2014). Briefly, activation of FXR in ileal enterocytes leads to the production and secretion of FGF15 into the hepatic portal circulation.…”

“…Briefly, activation of FXR in ileal enterocytes leads to the production and secretion of FGF15 into the hepatic portal circulation. FGF15 travels to the liver and activates its predominant receptor, FGFR4, on hepatocytes, which subsequently suppresses bile acid synthesis through the down-regulation of the gene expression of Cyp7a1 (Li et al, 2014). In agreement, these FGF15-mediated negative feedback mechanisms on bile acid production were observed in our studies.…”

“…In the liver, FGF15 binds to its predominant receptor, fibroblast growth factor receptor 4 (FGFR4), a tyrosine kinase receptor, which then activates the mitogen-activated protein kinases (MAPK) signaling pathway. This results in down regulation of the expression of the Cytochrome P450 7a1 ( Cyp7a1) gene which encodes a rate-limiting enzyme for bile acid synthesis (Inagaki et al, 2005; Song et al, 2009; Kong et al, 2012; Li et al, 2014). Therefore, FGF15 acts as a negative feedback factor maintaining bile acid homeostasis.…”

Mechanisms of enterohepatic fibroblast growth factor 15/19 signaling in health and disease

“…2). The liver abundantly expresses both b-Klotho and FGFR4 which together constitute one of the major receptor complexes mediating FGF15/19 signaling [8,[21][22][23][24]. It is widely accepted that inhibition of BA synthesis by FGF15/19 requires intact signaling via this receptor complex since mice deficient for either Fgfr4 or b-Klotho have increased BA synthesis and impaired feedback repression of Cyp7a1 [18,[25][26][27][28].…”