Cadmium Interferes With The Expression Of Lipid Metabolism Transporter And Its Cytotoxic Mechanism In Inhibiting Autophagy

Cadmium pollution in the environment is considered to be related to the occurrence of chronic liver disease,kidney disease,hypertension and other diseases.Many mechanistic animal and experimental data support a role for Cd in atherosclerosis including increased endothelial permeability by inhibiting cell proliferation and promoting cell death,and changing lipid metabolism.But the studies about Cd caused lipid metabolism disorder only revealedthat Cd could induce dyslipidaemia such as increasing cholesterol and triglyceride levels in blood.However,the molecular mechanism is still unknown.In this research,we focused on the effect of Cd on lipid transport protein.To explain the mechanism of Cd increased transport protein ABCA1?ATP-binding cassette transporter A1?expression and explore the biotoxicity mechanism of cadmium inhibiting protein degradation by different molecular biology approaches.In this study,wefeed ICR mice with normal dietcontainingdifferentCddosefor 28days for establishing mice model to simulate the phenomenon of environment Cd pollution.Then we used RT-qPCR to detect some genes involved in lipid metabolism and analyzed the effect of Cd on lipid transport protein expression by Western Blotting.Protein stability analysis found that Cd increased ABCA1 protein in HepG2was mainly by inhibiting lysosomal degradation pathway,which was also a reason that Cd inhibited autophagy flux and lead to cytotoxicity.Cd disordered the expression of lipidtransport protein in mice liver.1.Cd increased MTTP?Microsomal triglyceride transfer protein?expression,which has capable of transferring triglycerides.Cd decreased LDLR?Low-density lipoprotein receptor?expression in mice liver significantly.But,the regulatory mechanisms of Cd for LDLR and MTTP are still needed to be further studied in the cell model.2.Cd increased cholesterol transport protein ABCA1 expression in mice liver tissue and verified in mice liver cell and HepG2 cell models.The results indicated that Cd neutralized lysosomal acidity to inhibit lysosome degradation pathway of ABCA1protein,resulting in increased ABCA1 stability and accumulation on cell surface.Intracellular Ca²⁺chelator BAPTA/AMand ROS scavenger?TCP?can rescued lysosomal acidity,and to varying degrees to reversed Cd-inhibited ABCA1degradation.It suggested that Cd inhibited the lysosome function via Ca²⁺and ROS.In addition,we found that Cd induced autophagy signal LC3-?accumulated but P62protein accumulation in HepG2 and mRTEC.It indicated that autophagy flux namely autophagy degradation was impeded.Further,findings in mRTEC showed that Cd induced apoptosis by elevating intracellular Ca²⁺level and impairing autophagy.