Independent Repression of Bile Acid Synthesis and Activation of c-Jun N-terminal Kinase (JNK) by Activated Hepatocyte Fibroblast Growth Factor Receptor 4 (FGFR4) and Bile Acids

Abstract

The fibroblast growth factor (FGF) receptor complex is a regulator of adult organ homeostasis in addition to its central role in embryonic development and wound healing. FGF receptor 4 (FGFR4) is the sole FGFR receptor kinase that is significantly expressed in mature hepatocytes. Previously, we showed that mice lacking mouse FGFR4 (mR4 ؊/؊ ) exhibited elevated fecal bile acids, bile acid pool size, and expression of liver cholesterol 7␣-hydroxylase (CYP7A1), the rate-limiting enzyme for canonical neutral bile acid synthesis. To prove that hepatocyte FGFR4 was a negative regulator of cholesterol metabolism and bile acid synthesis independent of background, we generated transgenic mice overexpressing a constitutively active human FGFR4 (CahR4) in hepatocytes and crossed them with the FGFR4-deficient mice to generate CahR4/mR4 ؊/؊ mice. In mice expressing active FGFR4 in liver, fecal bile acid excretion was 64%, bile acid pool size was 47%, and Cyp7a1 expression was 10 -30% of wild-type mice. The repressed level of Cyp7a1 expression was resistant to induction by a high cholesterol diet relative to wild-type mice. Expression of CahR4 in mR4 ؊/؊ mouse livers depressed bile acid synthesis below wild-type levels from the elevated levels observed in mR4 ؊/؊ . Levels of phosphorylated cJun N-terminal kinase (JNK), which is part of a pathway implicated in bile acid-mediated repression of synthesis, was 30% of wild-type levels in mR4 ؊/؊ livers, whereas CahR4 livers exhibited an average 2-fold increase. However, cholate still strongly induced phospho-JNK in mR4 ؊/؊ livers. These results confirm that hepatocyte FGFR4 regulates bile acid synthesis by repression of Cyp7a1 expression. Hepatocyte FGFR4 may contribute to the repression of bile acid synthesis through JNK signaling but is not required for activation of JNK signaling by bile acids.

FGFR4 Prevents Hyperlipidemia and Insulin Resistance but Underlies High-Fat Diet–Induced Fatty Liver

“…Hepatocyte FGFR4 is the determinant of plasma lipid levels and fatty liver. To determine the contribution of hepatocyte FGFR4 to lipid and glucose metabolism, we examined the impact of overexpression of FGFR4 in hepatocytes driven by the albumin promoter in FVB mice (21). A constitutively active FGFR4 (caFGFR4) mutant was used to ensure a sustained signal and to bypass the need for an activating ligand.…”

“…Hepatocyte FGFR4 regulates cholesterol-to-bile acid synthesis in the liver by transcriptional downregulation of cholesterol 7␣-hydroxylase (CYP7A1), the rate-limiting enzyme for classical bile acid synthesis (20,21). A gut-to-liver FGF15/19-to-FGFR4 axis explains why only intestinal, compared with portal or intravenous, administration of bile acids represses hepatic cyp7a1 expression and bile acid synthesis (19).…”

Deletion of the ileal basolateral bile acid transporter identifies the cellular sentinels that regulate the bile acid pool

“…Uptake of bile acids that activate FXR by the ileal enterocyte induces the expression of fibroblast growth factor is (FGF15) (11)(12)(13). FGF15 is released into the portal circulation and then binds to the hepatocyte basolateral receptor FGFR4, leading to the repression of Cyp7A1 expression (8,(12)(13)(14)(15). In short, FGF15 is the link between FXR sensing of bile acids in enterocytes and expression of Cyp7A1 in hepatocytes.…”

Resolving the mechanism of bile acid negative-feedback regulation, a Journal of Lipid Research tradition

“…The other SHP-1-independent mechanism involves activation of the tyrosine kinase associated with fibroblast growth factor receptor 4 (FGFR4) (13). The FGFR4 ligands responsible for initiating repression of CYP7A1 are FGF15 (mouse) and FGF19 (human), which are both produced by intestinal ileal cells (14)(15)(16). The discovery that intestinal expression of FGF19 (17) and FGF15 (18) is induced by activation of FXR explains why bile acid negativefeedback regulation of CYP7A1 could not be reproduced in cell culture systems consisting only of hepatic parenchymal cells (19).…”