Identification of miRNAs involved in liver injury induced by chronic exposure to cadmium

To elaborate the molecular mechanism underlying the hepatotoxicity induced by chronic exposure to cadmium (Cd), a mouse model with hepatocyte-specific deletion of Ppp2r1a (encoding protein phosphatase 2 A Aα subunit, PP2A Aα) gene was used to investigate the effect of cadmium exposure on liver injury. The wild type littermates (WT) and PP2A Aα^-/- mice (KO) were treated with cadmium chloride (CdCl₂) at concentrations of 0 mg/L, 10 mg/L, 100 mg/L in drinking water for 3, 6 and 9 months (KO mice only for 9 months), respectively. The pathological findings were characterized by progressive inflammation, steatosis, and liver fibrosis upon treatment of CdCl₂ in a dose-response and time-dependent manner. Notably, PP2A Aα depletion leads to a more profound liver injury induced by CdCl₂ treatment. The transcriptome analysis in livers of KO mice revealed 20 differentially expressed microRNAs (miRNAs) appeared in both 3- and 9-month. Particularly, the alterations of miR-34a-5p, miR-345-5p, and miR-30e-5p expressions were implicated in the development of liver disease and correlated with the degree of liver injury induced by cadmium treatment. Further analysis indicated that miR-34a-5p, miR-345-5p, and miR-30e-5p might be involved in CdCl₂-induced liver injury, in part by dysregulation of lipid metabolism and inflammation. The in vitro studies showed that miR-34a-5p was involved in regulation of CdCl₂-induced cytotoxicity through directly targeted adiponectin receptor 2 (AdipoR2) mRNA. Taken together, we identified that specific miRNAs were implicated in hepatotoxicity induced by chronic exposure to CdCl₂. These findings also provide new insight into the role of PP2A in regulation of miRNAs-mediated liver injury.