Quercetin mitigates ethanol-induced hepatic steatosis in zebrafish via P2X7R-mediated PI3K/ Keap1/Nrf2 signaling pathway

• Published in: Journal of ethnopharmacology 2021-03, Vol.268, p.113569, Article 113569
• Main Authors: Zhao, Xingtao, Gong, Lihong, Wang, Cheng, Liu, Meichen, Hu, Naihua, Dai, Xuyang, Peng, Cheng, Li, Yunxia
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Antioxidants - pharmacology; Antioxidants - therapeutic use; Carrier Proteins - biosynthesis; Dose-Response Relationship, Drug; Ethanol - toxicity; Ethanol-induced hepatic steatosis; Fatty Liver - chemically induced; Fatty Liver - metabolism; Fatty Liver - prevention & control; Keap l; NF-E2-Related Factor 2 - biosynthesis; Nrf2; P2X7R; Phosphatidylinositol 3-Kinases - biosynthesis; PI3K; Purinergic P2X Receptor Antagonists; Quercetin; Quercetin - pharmacology; Quercetin - therapeutic use; Receptors, Purinergic P2X7 - biosynthesis; Signal Transduction - drug effects; Signal Transduction - physiology; Zebrafish; Zebrafish Proteins - biosynthesis
• ISSN: 0378-8741; 1872-7573
• DOI: 10.1016/j.jep.2020.113569

Ethnopharmacological relevanceQuercetin is the active component of the higher content in PCP, which exerts various biological activities such as anti-obesity effect, anti-inflammatory and anti-oxidant activities in alcoholic liver disease (ALD). P2X7 receptor (P2X7R) plays an important role in health and disease, which can be activated by extracellular ATP to induce a variety of downstream events, including lipid metabolism, inflammatory molecule release, oxidative stress. However, whether the mechanism of quercetin on ethanol-induced hepatic steatosis via P2X7R-mediated haven't been elucidated. Zebrafish transgenic (fabp10: EGFP) larvae were treated with 100 μM, 50 μM, 25 μM quercetin for 48 h at 3 days post fertilization (dpf), then soaked in 350 mmol/L ethanol for 32 h, treated with 1 mM ATP (P2X7R activator) for 30min. Serum lipids, liver steatosis, oxidative stress factors were respectively detected. The mRNA levels in the related pathways were measured by quantitative Real-Time PCR (RT-qPCR) to investigate the mechanisms. Quercetin improved the liver function via decreasing ALT, AST and γ-GT level of zebrafish with acute ethanol-induced hepatic steatosis and attenuated hepatic TG, TC accumulation. Additionally, quercetin significantly reduced the MDA content and suppressed the ethanol-induced reduction of hepatic oxidative stress biomarkers GSH, CAT and SOD and significantly down-regulated the expression of P2X7R, and up-regulated the expression of phosphatidylinositol 3-kinase (PI3K), Kelch like ECH associated protein1 (Keap1), Nuclear Factor E2 related factor 2 (Nrf2). Moreover, ATP stimulation activated P2X7R, which further mediated the mRNA expressions of PI3K, Keap1 and Nrf2. Quercetin exhibited hepatoprotective capacity in zebrafish model, via regulating P2X7R-mediated PI3K/Keap1/Nrf2 oxidative stress signaling pathway. [Display omitted] •Quercetin alleviated lipid accumulation in zebrafish.•Quercetin suppressed alcohol hepatosteatosis via PI3K/Keap1/Nrf2 signaling pathways.•ATP-activated P2X7R were involved in regulating oxidative stress in zebrafish with alcohol hepatosteatosis.