This study investigated if cadmium chloride (CdCl₂)-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), CdCl₂ (10 moml/L; drinking water), CdCl₂ + miR-21 antagomir (inhibitor) (16 mg/kg/first 3 days), and CdCl₂ + 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 CdCl₂-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 CdCl₂-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 CdCl₂-treated rats. Of note, levels of Nrf2 were negatively correlated with the transcription of miR-21. In conclusion: QUR prevents CdCl₂-induced hepatic steatosis and fibrosis mainly through attenuating its ability to upregulate miR-21, at least, by upregulation of Nrf2.

中文翻译：

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槲皮素通过下调 miR-21 的转录来预防氯化镉诱导的肝脂肪变性和纤维化

该研究调查了氯化镉 (CdCl ₂ ) 诱导的肝脂肪变性和纤维化以及槲皮素 (QUR) 的保护作用是否介导了调节 miR-21（一种已知的肝脏脂肪生成和纤维化 miRNA）的活性。雄性大鼠（n  = 8/组）分为对照、对照 + QUR（50 mg/kg；口服）、CdCl ₂（10 moml/L；饮用水）、CdCl ₂  + miR-21 antagomir（抑制剂）（16 mg/kg/前 3 天）和 CdCl ₂  + QUR（50 mg/kg）。每天进行20周的治疗。所有治疗均对空腹血糖和胰岛素水平没有影响。施用 miR-21 或 QUR 可防止 CdCl ₂-诱导的肝损伤，以及脂滴和胶原蛋白沉积。它们还降低了血清 ALT 和 AST 水平，并降低了血清和肝脏中 CdCl ₂中总胆固醇、甘油三酯和低密度脂蛋白的水平-处理过的大鼠。同时，它们降低了肝脏活性氧、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) 的肝脏水平，谷胱甘肽 (GSH) 和超氧化物歧化酶 (SOD)。这些影响与 SREBP1、TGF-β1、Smad3 和胶原蛋白 1A 的表达降低以及 PPARα、CPT1 和 smad7 的表达增加有关。有趣的是，QUR 显着降低了 miR-21 的水平，并增加了 Nrf2 的蛋白质水平和活性，以及​​对照和 CdCl ₂治疗大鼠肝脏中 GSH 和 SOD 的水平。值得注意的是，Nrf2 的水平与 miR-21 的转录呈负相关。结论：QUR 防止 CdCl ₂诱导肝脂肪变性和纤维化主要通过减弱其上调 miR-21 的能力，至少是通过上调 Nrf2。