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Apigenin-6-C-glucoside ameliorates MASLD in rodent models via selective agonism of adiponectin receptor 2.

التفاصيل البيبلوغرافية
العنوان: Apigenin-6-C-glucoside ameliorates MASLD in rodent models via selective agonism of adiponectin receptor 2.
المؤلفون: Khatoon S; Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, 226031, India., Das N; Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, 226031, India., Chattopadhyay S; Division of Biochemistry and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, 226031, India., Joharapurkar A; Zydus Research Center, Moraiya, Ahmedabad, 382213, Gujarat, India., Singh A; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India., Patel V; Zydus Research Center, Moraiya, Ahmedabad, 382213, Gujarat, India., Nirwan A; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, 226031, India., Kumar A; Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, India., Mugale MN; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, India., Mishra DP; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, 226031, India., Kumaravelu J; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India., Guha R; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Laboratory Animal Facility, CSIR-Central Drug Research Institute, Lucknow, 226031, India., Jain MR; Zydus Research Center, Moraiya, Ahmedabad, 382213, Gujarat, India., Chattopadhyay N; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India; Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, 226031, India., Sanyal S; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. Electronic address: sanyal@cdri.res.in.
المصدر: European journal of pharmacology [Eur J Pharmacol] 2024 Sep 05; Vol. 978, pp. 176800. Date of Electronic Publication: 2024 Jun 29.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE
أسماء مطبوعة: Publication: 2005- : Amsterdam : Elsevier Science
Original Publication: Amsterdam, North Holland Pub. Co.
مواضيع طبية MeSH: Receptors, Adiponectin*/agonists , Receptors, Adiponectin*/metabolism , Apigenin*/pharmacology , Apigenin*/therapeutic use , Glucosides*/pharmacology , Glucosides*/therapeutic use, 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
مستخلص: 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.)
فهرسة مساهمة: Keywords: AdipoR2 agonist; Adiponectin receptor; Apigenin-6-C-Glucoside; Isovitexin; MASLD; NAFLD; NASH
المشرفين على المادة: 0 (Receptors, Adiponectin)
7V515PI7F6 (Apigenin)
0 (Glucosides)
0 (ADIPOR2 protein, human)
EC 2.7.11.31 (AMP-Activated Protein Kinases)
تواريخ الأحداث: Date Created: 20240701 Date Completed: 20240725 Latest Revision: 20240729
رمز التحديث: 20240730
DOI: 10.1016/j.ejphar.2024.176800
PMID: 38950835
قاعدة البيانات: MEDLINE
الوصف
تدمد:1879-0712
DOI:10.1016/j.ejphar.2024.176800