Quercetin prevents cadmium chloride-induced hepatic steatosis and fibrosis by downregulating the transcription of miR-21

Abstract

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.

Keywords: NAFLD; Quercetin; cadmium; liver; mi2R1.