Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis

Abstract

The liver and intestine play crucial roles in maintaining bile acid homeostasis. Here, we demonstrate that fibroblast growth factor 15 (FGF15) signals from intestine to liver to repress the gene encoding cholesterol 7alpha-hydroxylase (CYP7A1), which catalyzes the first and rate-limiting step in the classical bile acid synthetic pathway. FGF15 expression is stimulated in the small intestine by the nuclear bile acid receptor FXR and represses Cyp7a1 in liver through a mechanism that involves FGF receptor 4 (FGFR4) and the orphan nuclear receptor SHP. Mice lacking FGF15 have increased hepatic CYP7A1 mRNA and protein levels and corresponding increases in CYP7A1 enzyme activity and fecal bile acid excretion. These studies define FGF15 and FGFR4 as components of a gut-liver signaling pathway that synergizes with SHP to regulate bile acid synthesis.

Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice

“…[14][15][16] Intestinal FXR has been shown to play a pivotal role in regulating hepatic bile salt synthesis and bile salt pool composition through promoting the production of fibroblast growth factor 15 (FGF15; FGF19 in humans) that inhibits bile salt synthesis in the liver. 17 In the present study, we reveal that agonism of intestinal FXR greatly enhances the flux of cholesterol through the TICE pathway in a manner that largely depends on ABCG5/G8 function in the intestine. The composition of the bile salt pool conceivably impacts the rate of cholesterol removal from the body via TICE.…”

Functional evolutionary history of the mouse Fgf gene family

“…In contrast, Fgf15 knockout mice die at variable times during embryonic and postnatal stages of development. FGF15 functions in the development of the cardiac outflow tract (Vincentz et al, 2005) but also acts as an endocrine hormone in postnatal life (Inagaki et al, 2005). Other Fgf knockout mice either are viable or die during postnatal stages (Table 1).…”

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

“…FXR is highly expressed in the liver and intestine and is activated by primary human and murine BAs, chenodeoxycholic acid, and cholic acid, while the rodent‐specific primary BA tauromuricholic acid antagonizes FXR activation. Furthermore, activation of FXR by BAs induces fibroblast growth factor 15/fibroblast growth factor receptor 4 signaling to repress cholesterol 7‐alpha hydroxylase (Cyp7A1) expression 31. Additionally, antagonizing intestinal FXR inhibits Srebp1c and has beneficial effects on lipid metabolism 32.…”

“…Hepatic expression of Cyp7A1 and Cyp8b1 is regulated by FXR, which is highly expressed in both ileum and liver 88. Intestinal FXR also regulates hepatic Cyp7A1 through fibroblast growth factor 15‐dependent mechanisms 31, 88. Therefore, the gut microbiota modulates FXR signaling in gut by repressing activity of Cyp7a1 in liver.…”