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Published on: November 16, 2011
Mebhydrolin ameliorates glucose homeostasis in type 2 diabetic mice by functioning as a selective FXR antagonist
Tong Zhao1, Jie Wang2, Anxu He1
1School of Medicine& Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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.
Insights
A novel Farnesoid X receptor (FXR) antagonist, Mebhydrolin, improves glucose homeostasis in type 2 diabetes (T2DM) mice. It suppresses gluconeogenesis and promotes glycogen synthesis by modulating specific molecular pathways, offering potential T2DM treatment.
Area of Science:
- Endocrinology and Metabolism
- Pharmacology
- Molecular Biology
Background:
- Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia and hyperlipidemia, leading to severe complications.
- Farnesoid X receptor (FXR) antagonism shows promise for improving glucose metabolism in T2DM, but mechanisms are unclear.
Purpose of the Study:
- To discover a new FXR antagonist.
- To investigate the mechanism by which FXR antagonism ameliorates glucose homeostasis in T2DM mice.
Main Methods:
- Screening FDA-approved drugs to identify FXR antagonist Mebhydrolin using SPR, MST, and AlphaScreen assays.
- Evaluating Mebhydrolin's efficacy in T2DM mouse models (db/db, HFD/STZ).
- Investigating molecular mechanisms via liver tissue analysis, primary hepatocytes, molecular docking, and molecular dynamics.
Main Results:
- Mebhydrolin ameliorated blood glucose homeostasis in T2DM mice.
- It suppressed hepatic gluconeogenesis and promoted glycogen synthesis via the FXR/miR-22-3p/PI3K/AKT pathway.
- Specific FXR residues (L291, M332, Y373) are crucial for Mebhydrolin binding, inducing structural shifts affecting downstream gene regulation.
Conclusions:
- A novel mechanism for FXR regulation of glucose metabolism in T2DM was revealed.
- Mebhydrolin demonstrates significant potential for T2DM treatment.
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