An intestinal farnesoid x receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice

Cen Xie, Changtao Jiang, Jingmin Shi, Xiaoxia Gao, Dongxue Sun, Lulu Sun, Ting Wang, Shogo Takahashi, Mallappa Anitha, Kristopher W. Krausz, Andrew D. Patterson, Frank J. Gonzalez

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Increasing evidence supports the view that intestinal farnesoid X receptor (FXR) is involved in glucose tolerance and that FXR signaling can be profoundly impacted by the gut microbiota. Selective manipulation of the gut microbiota-FXR signaling axis was reported to significantly impact glucose intolerance, but the precise molecular mechanism remains largely unknown. Here, caffeic acid phenethyl ester (CAPE), an over-The-counter dietary supplement and an inhibitor of bacterial bile salt hydrolase, increased levels of intestinal tauro-b-muricholic acid, which selectively suppresses intestinal FXR signaling. Intestinal FXR inhibition decreased ceramide levels by suppressing expression of genes involved in ceramide synthesis specifically in the intestinal ileum epithelial cells. The lower serum ceramides mediated decreased hepatic mitochondrial acetyl-CoA levels and pyruvate carboxylase (PC) activities and attenuated hepatic gluconeogenesis, independent of body weight change and hepatic insulin signaling in vivo; this was reversed by treatment of mice with ceramides or the FXR agonist GW4064. Ceramides substantially attenuated mitochondrial citrate synthase activities primarily through the induction of endoplasmic reticulum stress, which triggers increased hepatic mitochondrial acetyl-CoA levels and PC activities. These results reveal a mechanism by which the dietary supplement CAPE and intestinal FXR regulates hepatic gluconeogenesis and suggest that inhibiting intestinal FXR is a strategy for treating hyperglycemia.

Original languageEnglish (US)
Pages (from-to)613-626
Number of pages14
JournalDiabetes
Volume66
Issue number3
DOIs
StatePublished - Mar 1 2017

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Gluconeogenesis
Ceramides
Liver
Pyruvate Carboxylase
Acetyl-CoA Carboxylase
choloylglycine hydrolase
Dietary Supplements
Citrate (si)-Synthase
Body Weight Changes
Endoplasmic Reticulum Stress
Glucose Intolerance
Ileum
Hyperglycemia
Epithelial Cells
Insulin
Gene Expression
Glucose
Serum

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Xie, C., Jiang, C., Shi, J., Gao, X., Sun, D., Sun, L., ... Gonzalez, F. J. (2017). An intestinal farnesoid x receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice. Diabetes, 66(3), 613-626. https://doi.org/10.2337/db16-0663
Xie, Cen ; Jiang, Changtao ; Shi, Jingmin ; Gao, Xiaoxia ; Sun, Dongxue ; Sun, Lulu ; Wang, Ting ; Takahashi, Shogo ; Anitha, Mallappa ; Krausz, Kristopher W. ; Patterson, Andrew D. ; Gonzalez, Frank J. / An intestinal farnesoid x receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice. In: Diabetes. 2017 ; Vol. 66, No. 3. pp. 613-626.
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abstract = "Increasing evidence supports the view that intestinal farnesoid X receptor (FXR) is involved in glucose tolerance and that FXR signaling can be profoundly impacted by the gut microbiota. Selective manipulation of the gut microbiota-FXR signaling axis was reported to significantly impact glucose intolerance, but the precise molecular mechanism remains largely unknown. Here, caffeic acid phenethyl ester (CAPE), an over-The-counter dietary supplement and an inhibitor of bacterial bile salt hydrolase, increased levels of intestinal tauro-b-muricholic acid, which selectively suppresses intestinal FXR signaling. Intestinal FXR inhibition decreased ceramide levels by suppressing expression of genes involved in ceramide synthesis specifically in the intestinal ileum epithelial cells. The lower serum ceramides mediated decreased hepatic mitochondrial acetyl-CoA levels and pyruvate carboxylase (PC) activities and attenuated hepatic gluconeogenesis, independent of body weight change and hepatic insulin signaling in vivo; this was reversed by treatment of mice with ceramides or the FXR agonist GW4064. Ceramides substantially attenuated mitochondrial citrate synthase activities primarily through the induction of endoplasmic reticulum stress, which triggers increased hepatic mitochondrial acetyl-CoA levels and PC activities. These results reveal a mechanism by which the dietary supplement CAPE and intestinal FXR regulates hepatic gluconeogenesis and suggest that inhibiting intestinal FXR is a strategy for treating hyperglycemia.",
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Xie, C, Jiang, C, Shi, J, Gao, X, Sun, D, Sun, L, Wang, T, Takahashi, S, Anitha, M, Krausz, KW, Patterson, AD & Gonzalez, FJ 2017, 'An intestinal farnesoid x receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice', Diabetes, vol. 66, no. 3, pp. 613-626. https://doi.org/10.2337/db16-0663

An intestinal farnesoid x receptor-ceramide signaling axis modulates hepatic gluconeogenesis in mice. / Xie, Cen; Jiang, Changtao; Shi, Jingmin; Gao, Xiaoxia; Sun, Dongxue; Sun, Lulu; Wang, Ting; Takahashi, Shogo; Anitha, Mallappa; Krausz, Kristopher W.; Patterson, Andrew D.; Gonzalez, Frank J.

In: Diabetes, Vol. 66, No. 3, 01.03.2017, p. 613-626.

Research output: Contribution to journalArticle

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AU - Gonzalez, Frank J.

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