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Holter, M.M.* ; Chirikjian, M.K.* ; Briere, D.A.* ; Maida, A. ; Sloop, K.W.* ; Schoonjans, K. ; Cummings, B.P.*

Compound 18 improves glucose tolerance in a hepatocyte TGR5-dependent manner in mice.

Nutrients 12:2124 (2020)
Verlagsversion Forschungsdaten DOI
Open Access Gold
Creative Commons Lizenzvertrag
The bile acid receptor, TGR5, is a key regulator of glucose homeostasis, but the mechanisms by which TGR5 signaling improves glucose regulation are incompletely defined. In particular, TGR5 has an increasingly appreciated role in liver physiology and pathobiology; however, whether TGR5 signaling within the liver contributes to its glucoregulatory effects is unknown. Therefore, we investigated the role of hepatocyte TGR5 signaling on glucose regulation using a hepatocyte-specific TGR5 knockout mouse model. Hepatocyte-specificTgr5(Hep+/+)andTgr5(Hep-/-)mice were fed a high fat diet (HFD) for 7 weeks and then orally gavaged with three doses of a highly potent, TGR5-specific agonist, Compound 18 (10 mg/kg), or vehicle, over 72 h and underwent an oral glucose tolerance test (OGTT) after the last dose. Herein, we report that TGR5 mRNA and protein is present in mouse hepatocytes. Cumulative food intake, body weight, and adiposity do not differ betweenTgr5(Hep+/+)andTgr5(Hep-/-)mice with or without treatment with Compound 18. However, administration of Compound 18 improves glucose tolerance inTgr5(HEP+/+)mice, but not inTgr5(Hep-/-)mice. Further, this effect occurred independent of body weight and GLP-1 secretion. Together, these data demonstrate that TGR5 is expressed in hepatocytes, where it functions as a key regulator of whole-body glucose homeostasis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Hepatocyte ; Tgr5 ; Glucose Regulation; Bile-acid Receptor; Nf-kappa-b; Insulin Sensitivity; Tgr5 Agonist; Gpbar1 Tgr5; Metabolism; Activation; Secretion; Identification; Resistance
ISSN (print) / ISBN 2072-6643
e-ISSN 2072-6643
Zeitschrift Nutrients
Quellenangaben Band: 12, Heft: 7, Seiten: , Artikelnummer: 2124 Supplement: ,
Verlag MDPI
Verlagsort Basel
Begutachtungsstatus Peer reviewed