Abstract
Hexavalent chromium [Cr(VI)] is a serious environmental pollutant that threatens human life. Cr(VI) is widely used in industrial processes such as metallurgy, leather processing, and electroplating, which can enter the human body through the respiratory or digestive tracts, thus causing a number of human disease, including inflammation and cancer. Although it has been confirmed that oxidative stress is one of the primary mechanism of liver injury caused by Cr(VI) exposure, the related toxic target and effective intervention measures have not been found. Clusterin (CLU) is an acute phase response protein with cytoprotective and apoptosis-delaying effects, and its expression has been confirmed to increase significantly after exposure to Cr(VI). In this study, our data clearly indicates that Cr(VI) is capable of causing hepatocytes damage through the production of large amounts of reactive oxygen species (ROS), causing an increase in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In contrast, over expression of CLU was able to inhibit ROS production and alleviate Cr(VI)-induced liver injury. The specific mechanisms are that CLU acts on the protein kinase B (PKB/Akt)-Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor E2-related factor 2 (Nrf2) signaling pathway to release Nrf2 into the nucleus. This is to initiate the expression of a downstream protein, heme oxygenase 1 (HO-1), thereby attenuating the ubiquitination ability of Keap1 with Nrf2. We also demonstrated that CLU could affect oxidative stress through the Akt/Nrf2 pathway, which reduced the production of ROS induced by Cr(VI) and protected against Cr(VI)-induced oxidative stress-associated hepatotoxicity. This study demonstrates a mechanism of Cr(VI)-induced hepatotoxicity and indicates that CLU as an intervention target of oxidative stress can provide valuable experimental basis for the prevention and treatment of occupational diseases in Cr(VI)-exposed population. Under the state of Cr(VI)-induced oxidative stress, CLU though phosphorylation Akt, leading to Nrf2 dissociation from Keap1. Activated Nrf2 entered the nucleus and formed the next step, thus binding to the structure of the antioxidant response element ARE, which activated HO-1, resulting in the decrease in intracellular ROS.