Department of Food Science and Nutrition, College of Food and Agricultural Science, King Saud University, Riyadh, Saudi Arabia.
Nutrition and Food Science, Department of Physical Sport Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
Biofactors. 2021 May;47(3):489-505. doi: 10.1002/biof.1724. Epub 2021 Mar 17.
This study investigated if cadmium chloride (CdCl )-induced hepatic steatosis and fibrosis and the protective effect of quercetin (QUR) are mediated modulating the activity of miR-21, a known hepatic lipogenic and fibrotic miRNA. Male rats (n = 8/group) were divided as control, control + QUR (50 mg/kg; orally), CdCl (10 moml/L; drinking water), CdCl + miR-21 antagomir (inhibitor) (16 mg/kg/first 3 days), and CdCl + QUR (50 mg/kg). Treatments were conducted for 20 weeks, daily. All treatments showed no effect on fasting glucose and insulin levels. Administration of either miR-21 or QUR prevented CdCl -induced hepatic damage, as well as lipid droplets and collagen deposition. They also reduced serum levels of ALT and AST and decreased serum and hepatic levels of total cholesterol, triglycerides, and low-density lipoproteins in CdCl -treated rats. Concomitantly, they reduced hepatic levels of reactive oxygen species, malondialdehyde, interleukin-6, and tumor necrosis factor-α, suppressed the activation of NF-kb P65, and increased hepatic levels of nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione (GSH), and superoxide dismutase (SOD). These effects were associated with reduced expression of SREBP1, TGF-β1, Smad3, and collagen1 A and increased expression of PPARα, CPT1, and smad7. Interestingly, QUR significantly lowered levels of miR-21 and increased the protein levels and activity of Nrf2, as well as levels of GSH and SOD in the livers of both the control and CdCl -treated rats. Of note, levels of Nrf2 were negatively correlated with the transcription of miR-21. In conclusion: QUR prevents CdCl -induced hepatic steatosis and fibrosis mainly through attenuating its ability to upregulate miR-21, at least, by upregulation of Nrf2.
本研究旨在探讨氯化镉（CdCl ）诱导的肝脂肪变性和纤维化，以及槲皮素（QUR）的保护作用是否通过调节 miR-21 的活性来介导，miR-21 是一种已知的肝脂肪生成和纤维化 miRNA。雄性大鼠（n=8/组）分为对照组、对照组+QUR（50mg/kg；口服）、CdCl （10 moml/L；饮用水）、CdCl + miR-21 拮抗剂（抑制剂）（16mg/kg/前 3 天）和 CdCl + QUR（50mg/kg）。所有治疗均连续进行 20 周，每日一次。miR-21 或 QUR 的给药均能预防 CdCl 引起的肝损伤、脂滴和胶原沉积。它们还降低了血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平，降低了 CdCl 处理大鼠血清和肝组织中总胆固醇、甘油三酯和低密度脂蛋白的水平。同时，它们降低了肝组织中活性氧、丙二醛、白细胞介素-6 和肿瘤坏死因子-α的水平，抑制了 NF-kb P65 的激活，并增加了核因子红细胞 2 相关因子 2（Nrf2）、谷胱甘肽（GSH）和超氧化物歧化酶（SOD）的肝水平。这些作用与 SREBP1、TGF-β1、Smad3 和胶原 1 A 的表达减少以及 PPARα、CPT1 和 smad7 的表达增加有关。有趣的是，QUR 显著降低了 miR-21 的水平，增加了 Nrf2 的蛋白水平和活性，以及 GSH 和 SOD 的水平，无论是在对照组还是 CdCl 处理的大鼠的肝脏中。值得注意的是，Nrf2 的水平与 miR-21 的转录呈负相关。总之：QUR 主要通过降低其上调 miR-21 的能力来预防 CdCl 引起的肝脂肪变性和纤维化，至少通过上调 Nrf2 来实现。
