Ellagic acid ameliorates oxidative stress and insulin resistance in high glucose-treated HepG2 cells via miR-223/keap1-Nrf2 pathway
Open accessAbstract
As a promising new target, miR-233 may regulate oxidative stress by targeting keap1-Nrf2 system to affect the pathological process of liver injury in T2DM. Ellagic acid (EA) is versatile for protecting oxidative stress damage and metabolic disorders. In the present study, we investigated the effect of EA on oxidative stress and insulin resistance in high glucose-induced T2DM HepG2 cells and examined the role of miR-223/keap1-Nrf2 pathway in system. HepG2 cells were incubated in 30 mM of glucose, with or without EA (15 and 30 μM) or metformin (Met, 150 μM) for 12 h. Glucose consumption, phosphorylation of IRS1, Akt and ERK under insulin stimulation, ROS and O2− production, MDA level, SOD activity and miR-223 expression, as well as protein levels of keap1, Nrf2, HO-1, SOD1 and SOD2 were analyzed. Furthermore, dual luciferase reporter assay, miR-223 mimic and inhibitor were implemented in cellular studies to explore the possible mechanism. EA upregulated glucose consumption, IRS1, Akt and ERK phosphorylation under insulin stimulation, reduced ROS and O2− production and MDA level, and increased SOD activity in high glucose-exposed HepG2 cells. In addition, EA elevated miR-223 expression level, downregulated mRNA and protein levels of keap1, and upregulated Nrf2, HO-1, SOD1 and SOD2 protein levels in this cell model. What’s more, dual luciferase reporter assay, miR-223 mimic and inhibitor transfection confirmed that EA activated keap1-Nrf2 system via elevating miR-223. The miR-223, a negative regulator of keap1, represents an attractive therapeutic target in hepatic injury in T2DM. EA ameliorates oxidative stress and insulin resistance via miR-223-mediated keap1-Nrf2 activation in high glucose-induced T2DM HepG2 cells.
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IRS1, AKT, and ERK are key components of the insulin signaling pathway; impaired IRS1 signaling leads to decreased activation of AKT and subsequent dysregulation of ERK involved in insulin resistance and metabolic dysfunction.
“Insulin receptor substrate 1 (IRS1), protein kinase B (AKT), and ERK are the key components of the insulin signaling pathway; impaired IRS1 signaling leads to decreased activation of AKT and subsequent dysregulation of ERK involved in insulin resistance and metabolic dysfunction (Ding et al., 2019).”
From AD-Like Neuropsychiatric Dysfunction in a Mice Model Induced by a Combination of High-Fat Diet and Intraperitoneal Injection of Streptozotocin (2024) · cites this paper as Ding et al., 2019
Section 3.3 identifies IRS1 as connecting insulin receptor activation to downstream Akt and ERK pathways, and reports reduced phosphorylation of all three in high-glucose-treated HepG2 cells. The Discussion also describes this as impaired insulin signaling. Neither passage establishes the claimed sequence in which reduced Akt activation subsequently dysregulates ERK. (LLM, conf=0.85)
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- Authors
- Ding, X., Jian, T., Wu, Y., Zuo, Y., Li, J., Lv, H., Ma, L., Ren, B., Zhao, L., Li, W., & Chen, J.
- Affiliations
- Institute of Botany, Jiangsu Province and Chinese Academy of Sciences (CN)
- Nanjing Forestry University (CN)
- Corresponding author
- Li, Weilin
- Chen, Jian
- Venue
- Biomedicine & Pharmacotherapy
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 110
- Pages
- 85-94
- ISSN
- 0753-3322 (ISSN-L)
- OpenAlex
- W2900865405
- Cited by
- 258
- References
- 5
- Citations by year
- 2026: 22 · 2025: 37 · 2024: 62 · 2023: 44 · 2022: 40 · 2021: 29 · 2020: 18 · 2019: 5
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biomedicine & Pharmacotherapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (31770366, 81703224, 81773885)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Health Sciences › Nursing › Nutrition and Dietetics › Pomegranate: compositions and health benefits
- Keywords
- ellagic acid, miR-223, Nrf2/Keap1 pathway, oxidative stress, insulin resistance, type 2 diabetes, high glucose, HepG2 cells, liver injury, metformin, reactive oxygen species, lipid peroxidation, SOD1, manganese superoxide dismutase, heme oxygenase-1, microRNA
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Cell Survival, Dose-Response Relationship, Drug, Ellagic Acid, Glucose, Humans, Insulin Resistance, Signal Transduction, Reactive Oxygen Species, Oxidative Stress, MicroRNAs, NF-E2-Related Factor 2, Hep G2 Cells
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