The bile acid-activated receptors, nuclear farnesoid X receptor (FXR) and the membrane Takeda G-protein receptor 5 (TGR5), are known to improve glucose and insulin sensitivity in obese and diabetic mice. However, the metabolic roles of these two receptors and the underlying mechanisms are incompletely understood. Here we studied the effects of the dual FXR and TGR5 agonist INT-767 on hepatic bile acid synthesis and intestinal secretion of glucagon-like peptide-1 (GLP-1) in wild type, Fxr-/-, and Tgr5-/- mice. INT-767 efficaciously stimulated intracellular Ca2+ levels, cAMP activity, and GLP-1 secretion and improved glucose and lipid metabolism more than did the FXR-selective obeticholic acid and TGR5-selective INT-777 agonists. Interestingly, INT-767 reduced expression of the genes in the classic bile acid synthesis pathway but induced those in the alternative pathway, which is consistent with decreased tauro-cholic acid and increased tauro-muricholic acids in bile. Furthermore, FXR activation induced expression of FXR target genes including fibroblast growth factor 15, and unexpectedly Tgr5 and prohormone convertase 1/3 gene expression in the ileum. We identified an FXR responsive element on the Tgr5 gene promoter. Fxr-/- and Tgr5-/- mice exhibited reduced GLP-1 secretion, which was stimulated by INT-767 in the Tgr5-/- mice but not in the Fxr-/- mice. Our findings uncovered a novel mechanism in which INT-767 activation of FXR induces Tgr5 gene expression and increases Ca2+ levels and cAMP activity to stimulate GLP-1 secretion and improve hepatic glucose and lipid metabolism in high fat diet-induced obese mice. Activation of both FXR and TGR5 therefore, may represent an effective therapy for managing hepatic steatosis, obesity and diabetes.
from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2pm3qih
via IFTTT
Εγγραφή σε:
Σχόλια ανάρτησης (Atom)
Δημοφιλείς αναρτήσεις
-
Publication date: Available online 4 January 2018 Source: European Journal of Radiology Author(s): Peiyao Zhang, Jing Wang, Qin Xu, Zhen...
-
Publication date: March 2017 Source: Free Radical Biology and Medicine, Volume 104 from #AlexandrosSfakianakis via Alexandros G.Sfak...
-
Dtsch med Wochenschr DOI: 10.1055/s-0043-100054 Hintergrund und Fragestellung Ein etablierter Weg, die optimale Behandlung von Tumorpatien...
-
Antibodies, Vol. 9, Pages 21: Construction of Ant... In Vivo and In Vitro Evaluation of Bull Semen Pro... Vertebral artery fenestration mimi...
-
Abstract Purpose F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) is emerging to be a useful tool in supporting the diag...
-
Does CBD Oil Lower Blood Pressure? This article was originally published at SundayScaries." Madeline Taylor POSTED ON January 13, 20...
-
Publication date: December 2017 Source: Advances in Biological Regulation, Volume 66 Author(s): Lauren Rusnak, Haian Fu The mitogen-activ...
-
Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182, Butyric Acid from Probiotic Staphyloco...
-
Correction to: The IL-23p19/EBI3 heterodimeric cytokine termed IL-39 remains a theoretical cytokine in man The original article can be found...
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου