부산대학교 도서관

The bile acid (BA), tauroursodeoxycholic acid (TUDCA) regulates glucose homeostasis; however, it is not clear whether its effects on insulin signaling are due to its direct interaction with the insulin receptor (IR) or through activation of the G-coupled BA receptor, TGR5. We, herein, investigated whether the actions of TUDCA on glucose homeostasis occur via IR or TGR5 activation. Glucose homeostasis was evaluated in high-fat diet (HFD)-obese or control (CTL) mice, after 30 days or one intraperitoneal (ip) injection of 300 mg/kg TUDCA, respectively. Molecular docking was performed to investigate the potential binding of TUDCA on the IR and TGR5. After 30 days of TUDCA treatment, HFD mice exhibited improvements in glucose tolerance and insulin sensitivity, which were abolished when these rodents received the IR antagonist, S961. Molecular docking experiments showed that TUDCA demonstrates high binding affinity for TGR5 and IR and strongly interacts with the insulin binding sites 1 and 2 of the IR. Consistent with this potential agonist activity of TUDCA on IR, CTL mice displayed increased hepatic phosphorylation of AKT after an ip injection of TUDCA. This effect was not associated with altered glycemia in CTL mice and was dependent on IR activation, as S961 prevented hepatic AKT activation by TUDCA. Furthermore, TUDCA activated the hepatic protein kinase A (PKA) and cAMP response element-binding protein (CREB) pathway in CTL mice, even after the administration of S961. We provide novel evidence that TUDCA may be an agonist of the IR, in turn activating AKT and contributing, at least in part, to its beneficial effects upon glucose homeostasis. Besides its interaction with the TGR5 and activation of the PKA pathway in the liver, TUDCA also displays higher affinity for the insulin binding sites of the IR, which many contribute to its effect on insulin signaling, especially during the activation of the PI3K/AKT pathway. TUDCA: Tauroursodeoxycholic acid; IR: Insulin receptor; IRS: insulin receptor substrate; PI3K: phosphatidylinositol 3-kinase; PDK1: phosphoinositide-dependent protien kinase 1; AKT: protein kinase B; PKA: protein kinase A; TGR5: G protein-coupled bile acid receptor 1. [Display omitted] • We provide novel evidence that TUDCA interacts with the insulin receptor (IR). • IR activation contributes to the TUDCA-induced improvements in glucose tolerance observed in obese mice. • In silico studies predicted that TUDCA may interact with IR, with a higher affinity for binding site 2. • TUDCA enhances pAKT expression in the liver, via a mechanism dependent on IR activation. [ABSTRACT FROM AUTHOR]