title: An Intestinal Farnesoid X Receptor-Ceramide Signaling Axis Modulates Hepatic Gluconeogenesis in Mice.
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-β-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.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Cen
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China gonzalef@mail.nih.gov jiangchangtao@bjmu.edu.cn.|Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Jingmin
authors.initials: J
authors.lastname: Shi
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Gao
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Dongxue
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.|Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.|Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Shogo
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA.
authors.forename: Mallappa
authors.initials: M
authors.lastname: Anitha
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Patterson
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD gonzalef@mail.nih.gov jiangchangtao@bjmu.edu.cn.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000105:Acetyl Coenzyme A / Q000187:drug effects / Q000378:metabolism; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002109:Caffeic Acids / Q000494:pharmacology*; D002518:Ceramides / Q000378:metabolism*; D059305:Diet, High-Fat; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D005943:Gluconeogenesis / Q000187:drug effects*; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011766:Pyruvate Carboxylase / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013656:Taurocholic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000105:Acetyl Coenzyme A; D000581:Amidohydrolases; D002109:Caffeic Acids; D002518:Ceramides; D007328:Insulin; D007555:Isoxazoles; D010626:Phenylethyl Alcohol; D011766:Pyruvate Carboxylase; D018160:Receptors, Cytoplasmic and Nuclear; D013656:Taurocholic Acid; D000099150:Receptor, Farnesoid X-Activated; C037351:tauromuricholic acid; C023154:choloylglycine hydrolase; C055494:caffeic acid phenethyl ester; C412815:GW 4064