Bile acids as hormones: The FXR-FGF15/19 pathway

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

While it has long been recognized that bile acids are essential for solubilizing lipophilic nutrients in the small intestine, the discovery in 1999 that bile acids serve as ligands for the nuclear receptor farnesoid X receptor (FXR) opened the floodgates in terms of characterizing their actions as selective signaling molecules. Bile acids act on FXR in ileal enterocytes to induce the expression of fibroblast growth factor (FGF)15/19, an atypical FGF that functions as a hormone. FGF15/19 subsequently acts on a cell surface receptor complex in hepatocytes to repress bile acid synthesis and gluconeogenesis, and to stimulate glycogen and protein synthesis. FGF15/19 also stimulates gallbladder filling. Thus, the bile acid-FXR-FGF15/19 signaling pathway regulates diverse aspects of the postprandial enterohepatic response. Pharmacologically, this endocrine pathway provides exciting new opportunities for treating metabolic disease and bile acid-related disorders such as primary biliary cirrhosis and bile acid diarrhea. Both FXR agonists and FGF19 analogs are currently in clinical trials.

Original languageEnglish (US)
Pages (from-to)327-331
Number of pages5
JournalDigestive Diseases
Volume33
Issue number3
DOIs
StatePublished - Jun 9 2015

Fingerprint

Bile Acids and Salts
Hormones
Fibroblast Growth Factors
Gluconeogenesis
Biliary Liver Cirrhosis
Enterocytes
Metabolic Diseases
Cell Surface Receptors
Cytoplasmic and Nuclear Receptors
Gallbladder
Glycogen
Small Intestine
Hepatocytes
Diarrhea
Clinical Trials
Ligands
Food
Proteins

Keywords

  • CYP7A1
  • Fibroblast growth factor
  • Ileum
  • Liver
  • Nuclear receptor

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Bile acids as hormones : The FXR-FGF15/19 pathway. / Kliewer, Steven A.; Mangelsdorf, David J.

In: Digestive Diseases, Vol. 33, No. 3, 09.06.2015, p. 327-331.

Research output: Contribution to journalArticle

@article{b3dee24d7e2940edb27a0722803455f8,
title = "Bile acids as hormones: The FXR-FGF15/19 pathway",
abstract = "While it has long been recognized that bile acids are essential for solubilizing lipophilic nutrients in the small intestine, the discovery in 1999 that bile acids serve as ligands for the nuclear receptor farnesoid X receptor (FXR) opened the floodgates in terms of characterizing their actions as selective signaling molecules. Bile acids act on FXR in ileal enterocytes to induce the expression of fibroblast growth factor (FGF)15/19, an atypical FGF that functions as a hormone. FGF15/19 subsequently acts on a cell surface receptor complex in hepatocytes to repress bile acid synthesis and gluconeogenesis, and to stimulate glycogen and protein synthesis. FGF15/19 also stimulates gallbladder filling. Thus, the bile acid-FXR-FGF15/19 signaling pathway regulates diverse aspects of the postprandial enterohepatic response. Pharmacologically, this endocrine pathway provides exciting new opportunities for treating metabolic disease and bile acid-related disorders such as primary biliary cirrhosis and bile acid diarrhea. Both FXR agonists and FGF19 analogs are currently in clinical trials.",
keywords = "CYP7A1, Fibroblast growth factor, Ileum, Liver, Nuclear receptor",
author = "Kliewer, {Steven A.} and Mangelsdorf, {David J.}",
year = "2015",
month = "6",
day = "9",
doi = "10.1159/000371670",
language = "English (US)",
volume = "33",
pages = "327--331",
journal = "Digestive Diseases",
issn = "0257-2753",
publisher = "S. Karger AG",
number = "3",

}

TY - JOUR

T1 - Bile acids as hormones

T2 - The FXR-FGF15/19 pathway

AU - Kliewer, Steven A.

AU - Mangelsdorf, David J.

PY - 2015/6/9

Y1 - 2015/6/9

N2 - While it has long been recognized that bile acids are essential for solubilizing lipophilic nutrients in the small intestine, the discovery in 1999 that bile acids serve as ligands for the nuclear receptor farnesoid X receptor (FXR) opened the floodgates in terms of characterizing their actions as selective signaling molecules. Bile acids act on FXR in ileal enterocytes to induce the expression of fibroblast growth factor (FGF)15/19, an atypical FGF that functions as a hormone. FGF15/19 subsequently acts on a cell surface receptor complex in hepatocytes to repress bile acid synthesis and gluconeogenesis, and to stimulate glycogen and protein synthesis. FGF15/19 also stimulates gallbladder filling. Thus, the bile acid-FXR-FGF15/19 signaling pathway regulates diverse aspects of the postprandial enterohepatic response. Pharmacologically, this endocrine pathway provides exciting new opportunities for treating metabolic disease and bile acid-related disorders such as primary biliary cirrhosis and bile acid diarrhea. Both FXR agonists and FGF19 analogs are currently in clinical trials.

AB - While it has long been recognized that bile acids are essential for solubilizing lipophilic nutrients in the small intestine, the discovery in 1999 that bile acids serve as ligands for the nuclear receptor farnesoid X receptor (FXR) opened the floodgates in terms of characterizing their actions as selective signaling molecules. Bile acids act on FXR in ileal enterocytes to induce the expression of fibroblast growth factor (FGF)15/19, an atypical FGF that functions as a hormone. FGF15/19 subsequently acts on a cell surface receptor complex in hepatocytes to repress bile acid synthesis and gluconeogenesis, and to stimulate glycogen and protein synthesis. FGF15/19 also stimulates gallbladder filling. Thus, the bile acid-FXR-FGF15/19 signaling pathway regulates diverse aspects of the postprandial enterohepatic response. Pharmacologically, this endocrine pathway provides exciting new opportunities for treating metabolic disease and bile acid-related disorders such as primary biliary cirrhosis and bile acid diarrhea. Both FXR agonists and FGF19 analogs are currently in clinical trials.

KW - CYP7A1

KW - Fibroblast growth factor

KW - Ileum

KW - Liver

KW - Nuclear receptor

UR - http://www.scopus.com/inward/record.url?scp=84930581210&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930581210&partnerID=8YFLogxK

U2 - 10.1159/000371670

DO - 10.1159/000371670

M3 - Article

C2 - 26045265

AN - SCOPUS:84930581210

VL - 33

SP - 327

EP - 331

JO - Digestive Diseases

JF - Digestive Diseases

SN - 0257-2753

IS - 3

ER -