Intestinal Farnesoid X Receptor Signaling Modulates Metabolic Disease

Frank J. Gonzalez, Changtao Jiang, Cen Xie, Andrew David Patterson

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Farnesoid X receptor (FXR) regulates the synthesis, transport and enterohepatic circulation of bile acids (BA) by modulating the expression of related genes in the liver and small intestine. The composition of the gut microbiota is correlated with metabolic diseases, notably obesity and non-alcoholic fatty acid disease (NAFLD). Recent studies revealed that bacterial metabolism of BA can modulate FXR signaling in the intestine by altering the composition and concentrations of FXR agonist and antagonist. FXR agonist enhances while FXR antagonist suppresses obesity, NAFLD and insulin resistance. The role of intestinal FXR in metabolic disease was firmly established by the analysis of mice lacking FXR that are metabolic resistant to HFD-induced metabolic disease. This is mediated by FXR modulating in part the expression of genes involved in ceramide synthesis in the small intestine. In ileum of obese mice due to the presence of endogenous FXR agonists produced in the liver, these genes are activated, while in mice with altered levels of specific gut bacteria, levels of an FXR antagonist, tauro-β-muricholic acid (T-β-MCA) increase and FXR signaling and ceramide synthesis are repressed. T-β-MCA, which is metabolized in wild-type mice, led to the discovery of glycine-β-muricholic acid (Gly-MCA) that is stable in the intestine and a potent inhibitor of FXR signaling. These studies reveal that ceramides produced in the ileum under the control of FXR, influence metabolic disease, and suggest that novel FXR antagonist such as Gly-MCA that specifically inhibit intestine FXR, could serve as potential drug for the treatment of metabolic disease.

Original languageEnglish (US)
Pages (from-to)178-184
Number of pages7
JournalDigestive Diseases
Volume35
Issue number3
DOIs
StatePublished - Mar 1 2017

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Metabolic Diseases
Ceramides
Intestines
Bile Acids and Salts
Ileum
Glycine
Small Intestine
Obesity
Enterohepatic Circulation
Gene Expression
Obese Mice
Liver
Insulin Resistance
Fatty Acids
Bacteria
muricholic acid
Pharmaceutical Preparations
Genes
Non-alcoholic Fatty Liver Disease

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

Gonzalez, Frank J. ; Jiang, Changtao ; Xie, Cen ; Patterson, Andrew David. / Intestinal Farnesoid X Receptor Signaling Modulates Metabolic Disease. In: Digestive Diseases. 2017 ; Vol. 35, No. 3. pp. 178-184.
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Intestinal Farnesoid X Receptor Signaling Modulates Metabolic Disease. / Gonzalez, Frank J.; Jiang, Changtao; Xie, Cen; Patterson, Andrew David.

In: Digestive Diseases, Vol. 35, No. 3, 01.03.2017, p. 178-184.

Research output: Contribution to journalArticle

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