Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling

Agostino Di Ciaula, Leonilde Bonfrate, Jacek Baj, Mohamad Khalil, Gabriella Garruti, Frans Stellaard, Helen H. Wang, David Q.H. Wang, Piero Portincasa

Research output: Contribution to journalReview articlepeer-review

Abstract

Bile acids (BA) are amphiphilic molecules synthesized in the liver (primary BA) starting from cholesterol. In the small intestine, BA act as strong detergents for emulsification, solubilization and absorption of dietary fat, cholesterol, and lipid-soluble vitamins. Primary BA escaping the active ileal re-absorption undergo the microbiota-dependent biotransformation to secondary BA in the colon, and passive diffusion into the portal vein towards the liver. BA also act as signaling molecules able to play a systemic role in a variety of metabolic functions, mainly through the activation of nuclear and membrane-associated receptors in the intestine, gallbladder, and liver. BA homeostasis is tightly controlled by a complex interplay with the nuclear receptor farnesoid X receptor (FXR), the enterokine hormone fibroblast growth factor 15 (FGF15) or the human ortholog FGF19 (FGF19). Circulating FGF19 to the FGFR4/β-Klotho receptor causes smooth muscle relaxation and refilling of the gallbladder. In the liver the binding activates the FXR-small heterodimer partner (SHP) pathway. This step suppresses the unnecessary BA synthesis and promotes the continuous enterohepatic circulation of BAs. Besides BA homeostasis, the BA-FXR-FGF19 axis governs several metabolic processes, hepatic protein, and glycogen synthesis, without inducing lipogenesis. These pathways can be disrupted in cholestasis, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Thus, targeting FXR activity can represent a novel therapeutic approach for the prevention and the treatment of liver and metabolic diseases.

Original languageEnglish (US)
Article number4950
JournalNutrients
Volume14
Issue number23
DOIs
StatePublished - Dec 2022
Externally publishedYes

Keywords

  • agonist
  • bile acids
  • FGF15/19
  • FXR
  • nonalcoholic fatty liver disease
  • nuclear receptors

ASJC Scopus subject areas

  • Food Science
  • Nutrition and Dietetics

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