Role of Autophagy in Cadmium-Induced Hepatotoxicity and Liver Diseases

Abstract

Cadmium (Cd) is a toxic pollutant that is associated with several severe human diseases. Cd can be easily absorbed in significant quantities from air contamination/industrial pollution, cigarette smoke, food, and water and primarily affects the liver, kidney, and lungs. Toxic effects of Cd include hepatotoxicity, nephrotoxicity, pulmonary toxicity, and the development of various human cancers. Cd is also involved in the development and progression of fatty liver diseases and hepatocellular carcinoma. Cd affects liver function via modulation of cell survival/proliferation, differentiation, and apoptosis. Moreover, Cd dysregulates hepatic autophagy, an endogenous catabolic process that detoxifies damaged cell organelles or dysfunctional cytosolic proteins through vacuole-mediated sequestration and lysosomal degradation. In this article, we review recent developments and findings regarding the role of Cd in the modulation of hepatotoxicity, autophagic function, and liver diseases at the molecular level.

Figure 1

The schematic model represents the different environmental sources of Cd that impact liver toxicity. Cd accumulation increases liver toxicity and induces liver damage. Cd accumulation increases the expression of ALT, AST, GGT, MDA, and peroxidase activities, a prominent liver damage marker. On the other hand, pre- or postexposure with chelating agents, metals like Se and several phytochemicals could reverse the Cd-mediated hepatic toxicity/damage.

Figure 2

The schematic model represents the role of Cd in liver inflammation and the development of NASH, cirrhosis, and HCC. Cd deposition in the liver downregulates glutathione production and increases oxidative stress, mitochondrial dysfunction, and DNA damage. Cd deposition also enhances hepatic steatosis, which leads to an increase in severe liver lesions/damage and HCC progression.

Figure 3

Cd increases HCC cell steatosis. (a) Normal liver HepaRG cells and HCC HepG2 cells were exposed with 10 nM and 100 nM of Cd for 30 h and cells were treated with oleic acid (100 μM) for an additional 24 h. Cells were fixed with paraformaldehyde and stained with oil red O and images were captured and presented. (b) The effect of Cd on oleic acid-mediated lipid droplet formation was quantified and plotted. ^∗P < 0.05, ^∗∗∗P < 0.001 compared with oleic acid- (OA-) treated cells.

Figure 4

A schematic model represents a dual role of Cd in autophagy regulation in the liver. Low concentrations of Cd exposure increase ER and oxidative stress in the liver and the expression of autophagy regulatory components such as ATG7, ATG4, p62, LC3B, and Beclin-1, leading to increased function autophagy and reduced Cd-mediated liver toxicity. In contrast, at higher concentrations, there is Cd-induced defective autophagy by increasing lysosomal acidification and by blocking autophagosome-lysosome fusion, leading to increased liver steatosis, NAFLD, and HCC development.