1. Apigenin-6-C-glucoside ameliorates MASLD in rodent models via selective agonism of adiponectin receptor 2.
- Author
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Khatoon S, Das N, Chattopadhyay S, Joharapurkar A, Singh A, Patel V, Nirwan A, Kumar A, Mugale MN, Mishra DP, Kumaravelu J, Guha R, Jain MR, Chattopadhyay N, and Sanyal S
- Subjects
- Animals, Humans, Mice, Male, Hep G2 Cells, HEK293 Cells, Disease Models, Animal, Mice, Inbred C57BL, Oxidative Stress drug effects, Liver drug effects, Liver metabolism, Liver pathology, AMP-Activated Protein Kinases metabolism, Receptors, Adiponectin agonists, Receptors, Adiponectin metabolism, Apigenin pharmacology, Apigenin therapeutic use, Glucosides pharmacology, Glucosides therapeutic use
- Abstract
Adiponectin plays key roles in energy metabolism and ameliorates inflammation, oxidative stress, and mitochondrial dysfunction via its primary receptors, adiponectin receptors -1 and 2 (AdipoR1 and AdipoR2). Systemic depletion of adiponectin causes various metabolic disorders, including MASLD; however adiponectin supplementation is not yet achievable owing to its large size and oligomerization-associated complexities. Small-molecule AdipoR agonists, thus, may provide viable therapeutic options against metabolic disorders. Using a novel luciferase reporter-based assay here, we have identified Apigenin-6-C-glucoside (ACG), but not apigenin, as a specific agonist for the liver-rich AdipoR isoform, AdipoR2 (EC
50 : 384 pM) with >10000X preference over AdipoR1. Immunoblot analysis in HEK-293 overexpressing AdipoR2 or HepG2 and PLC/PRF/5 liver cell lines revealed rapid AMPK, p38 activation and induction of typical AdipoR targets PGC-1α and PPARα by ACG at a pharmacologically relevant concentration of 100 nM (reported cMax in mouse; 297 nM). ACG-mediated AdipoR2 activation culminated in a favorable modulation of key metabolic events, including decreased inflammation, oxidative stress, mitochondrial dysfunction, de novo lipogenesis, and increased fatty acid β-oxidation as determined by immunoblotting, QRT-PCR and extracellular flux analysis. AdipoR2 depletion or AMPK/p38 inhibition dampened these effects. The in vitro results were recapitulated in two different murine models of MASLD, where ACG at 10 mg/kg body weight robustly reduced hepatic steatosis, fibrosis, proinflammatory macrophage numbers, and increased hepatic glycogen content. Together, using in vitro experiments and rodent models, we demonstrate a proof-of-concept for AdipoR2 as a therapeutic target for MASLD and provide novel chemicobiological insights for the generation of translation-worthy pharmacological agents., Competing Interests: Declaration of competing interest We hereby declare that none of the authors has any competing interest pertaining to this study. 3 authors, Amit Joharapurakar, Mukul R Jain, and Vishal Patel are employees of Zydus Research center, the R&D wing of Zydus Lifesciences Ltd. The collaboration between CDRI (communicating institution) and Zydus Research Center was strictly academic., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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