Bile Acids as Hormones: The FXR-FGF15/19 Pathway

Area of Science:

• Endocrinology
• Hepatology
• Gastroenterology

Background:

• Bile acids are crucial for nutrient absorption in the small intestine.
• The discovery of bile acids as ligands for the farnesoid X receptor (FXR) in 1999 revealed their signaling roles.
• FXR activation by bile acids modulates key metabolic and digestive processes.

Purpose of the Study:

• To elucidate the signaling pathway initiated by bile acids acting on FXR.
• To characterize the downstream effects of this pathway on hepatic and intestinal functions.
• To explore the therapeutic potential of targeting the bile acid-FXR-FGF15/19 axis.

Main Methods:

• Investigated the interaction between bile acids and FXR in ileal enterocytes.
• Analyzed the induction of fibroblast growth factor (FGF)15/19 expression.
• Examined the effects of FGF15/19 on hepatocyte functions, including bile acid synthesis and gluconeogenesis.

Main Results:

• Bile acids activate FXR in the ileum, leading to FGF15/19 production.
• FGF15/19 acts on hepatocytes to inhibit bile acid synthesis and gluconeogenesis.
• FGF15/19 also promotes glycogen and protein synthesis and stimulates gallbladder filling.

Conclusions:

• The bile acid-FXR-FGF15/19 pathway is a critical regulator of the postprandial enterohepatic response.
• This endocrine pathway presents novel pharmacological targets for metabolic diseases and bile acid-related disorders.
• FXR agonists and FGF19 analogs are under clinical investigation for therapeutic applications.