title: Intestinal Bile Acid Composition Modulates Prohormone Convertase 1/3 (PC1/3) Expression and Consequent GLP-1 Production in Male Mice.
abstract: Besides an established medication for hypercholesterolemia, bile acid binding resins (BABRs) present antidiabetic effects. Although the mechanisms underlying these effects are still enigmatic, glucagon-like peptide-1 (GLP-1) appears to be involved. In addition to a few reported mechanisms, we propose prohormone convertase 1/3 (PC1/3), an essential enzyme of GLP-1 production, as a potent molecule in the GLP-1 release induced by BABRs. In our study, the BABR colestimide leads to a bile acid-specific G protein-coupled receptor TGR5-dependent induction of PC1/3 gene expression. Here, we focused on the alteration of intestinal bile acid composition and consequent increase of total TGR5 agonistic activity to explain the TGR5 activation. Furthermore, we demonstrate that nuclear factor of activated T cells mediates the TGR5-triggered PC1/3 gene expression. Altogether, our data indicate that the TGR5-dependent intestinal PC1/3 gene expression supports the BABR-stimulated GLP-1 release. We also propose a combination of BABR and dipeptidyl peptidase-4 inhibitor in the context of GLP-1-based antidiabetic therapy.
authors.affiliation: Department of Internal Medicine (K.M., T.S., J.-i.I., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan; and Graduate School of Media and Governance (M.W.), Faculty of Environment and Information Studies, Keio University, Kanagawa 252-0882, Japan.
authors.forename: Kohkichi
authors.initials: K
authors.lastname: Morimoto
authors.affiliation: Department of Internal Medicine (K.M., T.S., J.-i.I., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan; and Graduate School of Media and Governance (M.W.), Faculty of Environment and Information Studies, Keio University, Kanagawa 252-0882, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Internal Medicine (K.M., T.S., J.-i.I., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan; and Graduate School of Media and Governance (M.W.), Faculty of Environment and Information Studies, Keio University, Kanagawa 252-0882, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Sugizaki
authors.affiliation: Department of Internal Medicine (K.M., T.S., J.-i.I., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan; and Graduate School of Media and Governance (M.W.), Faculty of Environment and Information Studies, Keio University, Kanagawa 252-0882, Japan.
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Irie
authors.affiliation: Department of Internal Medicine (K.M., T.S., J.-i.I., H.I.), School of Medicine, Keio University, Tokyo 160-8582, Japan; and Graduate School of Media and Governance (M.W.), Faculty of Environment and Information Studies, Keio University, Kanagawa 252-0882, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D059305:Diet, High-Fat; D004811:Epichlorohydrin / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000187:drug effects* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D051379:Mice; D045664:Proprotein Convertase 1 / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects* / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000378:metabolism; D012117:Resins, Synthetic / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015430:Weight Gain / Q000187:drug effects
chemical_list: D001647:Bile Acids and Salts; D001786:Blood Glucose; C513561:Gpbar1 protein, mouse; D007093:Imidazoles; D007328:Insulin; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D012117:Resins, Synthetic; C417427:colestimide; D004811:Epichlorohydrin; D052216:Glucagon-Like Peptide 1; D045664:Proprotein Convertase 1