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Cited by 137Liver Disease Diagnosis and TreatmentSirtuins and Resveratrol in MedicineFlavonoids in Medical Research

Naringenin alleviates nonalcoholic steatohepatitis in middle-aged Apoe−/−mice: role of SIRT1

Hua, Yi Qiao, Zeng, Yi, Xu, Jin, Xu, Xiao Le·2021·Phytomedicine
DOI 10.1016/j.phymed.2020.153412
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Abstract

Background Naringenin is naturally isolated from citrus fruits possessing many pharmacological activities. However, little is known about the effect of naringenin on nonalcoholic steatohepatitis (NASH) in the model of metabolic syndrome.Purpose The present study is aimed to investigate the effect of naringenin on NASH in 12-mo-old male ApoE-/- mice and its possible underlying mechanism.Methods In vivo, 12-mo-old male ApoE-/- mice were administrated with naringenin by intragastric gavage for 12 weeks. At the end of experiment, the blood samples and liver tissues were collected. Metabolic parameters in serum, levels of triglyceride, cholesterol and hydroxyproline, activities of antioxidant enzymes, and content of inflammatory cytokines (TNF-α and IL-6) in liver were examined by corresponding assay kits. Pathological changes in liver were observed by hematoxylin-eosin, oil red O, masson's trichrome, picro-sirius red and senescence β-galactosidase staining. Dihydroethidium was used for detection of reactive oxygen species (ROS). In vitro, AML-12 cells were treated with oleic acid in the presence or absence of naringenin for 24 h. Transfection of SIRT1 siRNA was also conducted in vitro. Lipid accumulation, cellular ROS generation, malondialdehyde content, antioxidant enzyme activities and secretion levels of TNF-α and IL-6 were examined. Both in vivo and in vitro, gene expressions were detected by real-time PCR or western blot.Results Naringenin administration improved metabolic parameters, suppressed hepatic steatosis, regulated expression of genes involved in lipid metabolism (FASN, SCD1, PPARα and CPT1α), reduced hepatic fibrosis and cell senescence, inhibited hepatic inflammation as evidenced by the decreased macrophage recruitment and content of TNF-α and IL-6, and reduced hepatic oxidative stress by suppressing ROS generation and normalizing activities of antioxidant enzymes. Notably, naringenin administration increased hepatic SIRT1 protein expression and activity along with the increased deacetylation of liver kinase B1 (LKB1), PGC1α and NF-κB. In vitro study, the benefits of naringenin on lipid accumulation, oxidative stress and inflammation were diminished by SIRT1 siRNA transfection.Conclusions These results indicate that naringenin administration may be a potential curative therapy for NASH treatment and the activation of hepatic SIRT1-mediated signaling cascades is involved in its beneficial effects.

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  • Beside antioxidant activity, flavonoids have anti-inflammatory, vasodilator, anticoagulant, cardioprotective, anti-diabetic, neuroprotective, and anti-obesity activities, making them of interest as anti-aging compounds.

    “Beside the antioxidant activity, flavonoids have anti-inflammatory, vasodilator, anticoagulant, cardioprotective, anti-diabetic, neuroprotective, and anti-obesity activities, which make them of great interest as anti-aging compounds (Table 3) [228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257].”

    From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [230]

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Authors
Hua, Y. Q., Zeng, Y., Xu, J., & Xu, X. L.
Affiliations
Nantong University (CN)
Corresponding author
Xu, Xiao Le
ORCID
Venue
Phytomedicine
Publisher
Elsevier BV
Published
2021-01
Volume
81
Pages
153412
ISSN
0944-7113 (ISSN-L)
DOI
10.1016/j.phymed.2020.153412
OpenAlex
W3105272009
Cited by
137
References
36
Citations by year
2026: 36 · 2025: 29 · 2024: 27 · 2023: 24 · 2022: 15 · 2021: 5
FWCI
7.88
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Phytomedicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
Keywords
naringenin, nonalcoholic steatohepatitis, SIRT1, metabolic syndrome, hepatic steatosis, liver fibrosis, oxidative stress, inflammation, lipid metabolism, oleic acid-induced lipid accumulation, LKB1, PGC-1α, NF-κB, macrophage recruitment, citrus flavonoids, ApoE-deficient mice, AML12 cells
MeSH terms
Mice, Knockout, ApoE, Animals, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Nuclear Proteins, Transcription Factors, NF-kappa B, Reactive Oxygen Species, Oxidative Stress, Flavanones, Lipid Metabolism, Mice, Sirtuin 1, Non-alcoholic Fatty Liver Disease

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