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Tytuł pozycji:

Mebhydrolin ameliorates glucose homeostasis in type 2 diabetic mice by functioning as a selective FXR antagonist.

Tytuł:
Mebhydrolin ameliorates glucose homeostasis in type 2 diabetic mice by functioning as a selective FXR antagonist.
Autorzy:
Zhao T; School of Medicine& Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Wang J; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
He A; School of Medicine& Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Wang S; School of Medicine& Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Chen Y; School of Medicine& Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Lu J; School of Medicine& Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Lv J; School of Medicine& Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Li S; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
Wang J; School of Medicine& Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Qian M; School of Medicine& Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: .
Li H; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address: .
Shen X; School of Medicine& Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: .
Źródło:
Metabolism: clinical and experimental [Metabolism] 2021 Jun; Vol. 119, pp. 154771. Date of Electronic Publication: 2021 Apr 05.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Publication: New York, NY : Elsevier Inc.
Original Publication: New York, Grune & Stratton.
MeSH Terms:
Carbolines/*therapeutic use
Diabetes Mellitus, Type 2/*drug therapy
Glucose/*metabolism
Receptors, Cytoplasmic and Nuclear/*antagonists & inhibitors
Animals ; Blood Glucose/drug effects ; Blood Glucose/metabolism ; Carbolines/chemistry ; Carbolines/pharmacokinetics ; Cells, Cultured ; Diabetes Mellitus, Experimental/chemically induced ; Diabetes Mellitus, Experimental/drug therapy ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Type 2/chemically induced ; Diabetes Mellitus, Type 2/metabolism ; Gluconeogenesis/drug effects ; Gluconeogenesis/genetics ; HEK293 Cells ; Homeostasis/drug effects ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Molecular Docking Simulation ; Protein Interaction Domains and Motifs ; Receptors, Cytoplasmic and Nuclear/chemistry ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Streptozocin
Contributed Indexing:
Keywords: Farnesoid X receptor; Gluconeogenesis; Glycogen synthesis; Mebhydrolin; Type 2 diabetes; miR-22-3p
Substance Nomenclature:
0 (Blood Glucose)
0 (Carbolines)
0 (Receptors, Cytoplasmic and Nuclear)
0C5V0MRU6P (farnesoid X-activated receptor)
5W494URQ81 (Streptozocin)
9SUK9B7XVY (mebhydroline)
IY9XDZ35W2 (Glucose)
Entry Date(s):
Date Created: 20210408 Date Completed: 20210624 Latest Revision: 20210624
Update Code:
20240104
DOI:
10.1016/j.metabol.2021.154771
PMID:
33831422
Czasopismo naukowe
Introduction: Type 2 diabetes mellitus (T2DM) is a chronic disease with hallmarks of hyperglycemia and hyperlipidemia. Long-term hyperglycemia damages the functions of multiple tissues and organs leading to a series of complications and disability or even death. Nuclear receptor farnesoid X receptor (FXR) antagonism has been recently discovered to exhibit beneficial effect on glucose metabolism in T2DM mice, although the underlying mechanisms remain unclear. Here, we performed the study on the discovery of new FXR antagonist and investigated the mechanism underlying the amelioration of FXR antagonism on glucose homeostasis in T2DM mice by using the determined FXR antagonist as a probe.
Methods: FXR antagonist Mebhydrolin was discovered by screening against the lab in-house FDA approved drug library through surface plasmon resonance (SPR), microscale thermophoresis (MST), AlphaScreen, mammalian one-hybrid and transactivation assays. Activity of Mebhydrolin in improving glucose homeostasis was evaluated in db/db and HFD/STZ-induced T2DM mice, and the mechanisms governing the regulation of Mebhydrolin were investigated by assays of immunostaining, Western blot, ELISA, RT-PCR against liver tissues of both T2DM mice and the T2DM mice with liver-specific FXR knockdown injected via adeno-associated-virus AAV-FXR-RNAi and mouse primary hepatocytes. Finally, molecular docking and molecular dynamics (MD) technology-based study was performed to investigate the structural basis for the antagonistic regulation of Mebhydrolin against FXR at an atomic level.
Findings: Mebhydrolin ameliorated blood glucose homeostasis in T2DM mice by both suppressing hepatic gluconeogenesis via FXR/miR-22-3p/PI3K/AKT/FoxO1 pathway and promoting glycogen synthesis through FXR/miR-22-3p/PI3K/AKT/GSK3β pathway. Structurally, residues L291, M332 and Y373 of FXR were required for Mebhydrolin binding to FXR-LBD, and Mebhydrolin induced H2 and H6 shifting of FXR potently affecting the regulation of the downstream target genes.
Conclusions: Our work has revealed a novel mode for the regulation of FXR against glucose metabolism in T2DM mice and highlighted the potential of Mebhydrolin in the treatment of T2DM.
Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.
(Copyright © 2021 Elsevier Inc. All rights reserved.)

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