Chronic Over-expression of Fibroblast Growth Factor 21 Increases Bile Acid Biosynthesis by Opposing FGF15/19 Action

Jun Zhang, Jamila Gupte, Yan Gong, Jennifer Weiszmann, Yuan Zhang, Ki Jeong Lee, William G. Richards, Yang Li

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Pharmacological doses of fibroblast growth factor (FGF) 21 effectively normalize glucose, lipid and energy homeostasis in multiple animal models with many benefits translating to obese humans with type 2 diabetes. However, a role for FGF21 in the regulation of bile acid metabolism has not been reported. Herein, we demonstrate AAV-mediated FGF21 overexpression in mice increases liver expression of the key bile acid producing enzyme, Cyp7a1, resulting in an increased bile acid pool. Furthermore, in cholecystectomized mice, FGF21-mediated bile acid pool increase led to increased transit of bile acids into colon. We elucidate that the mechanism of FGF21 induced bile acid changes is mainly through antagonizing FGF15/19 function on liver βKlotho/FGFR4 receptor complex; thus inhibiting FGF15/19-mediated suppression of Cyp7a1 expression. In conclusion, these data reveal a previously unidentified role for FGF21 on bile acid metabolism and may be relevant to understand the effects of FGF21 analogs in clinical studies.

Original languageEnglish (US)
Pages (from-to)173-183
Number of pages11
JournalEBioMedicine
Volume15
DOIs
StatePublished - Feb 1 2017

Keywords

  • Bile acid metabolism
  • FGF19
  • FGF21
  • FGFR4
  • βKlotho

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Zhang, J., Gupte, J., Gong, Y., Weiszmann, J., Zhang, Y., Lee, K. J., Richards, W. G., & Li, Y. (2017). Chronic Over-expression of Fibroblast Growth Factor 21 Increases Bile Acid Biosynthesis by Opposing FGF15/19 Action. EBioMedicine, 15, 173-183. https://doi.org/10.1016/j.ebiom.2016.12.016