Abstract
Improper treatment of a large amount of industrial waste makes hexavalent chromium [Cr(VI)] seriously pollute the atmosphere, soil and water, and enter the food chain, seriously affecting the health of workers and local residents. We previously proved that Clusterin (CLU) can inhibit the apoptosis of L02 hepatocytes induced by Cr(VI) through mitochondrial pathway, but the associated molecular mechanism has not been further studied. Mitochondrial biogenesis is an important step in mitochondrial damage repair, but the mechanism of mitochondrial biogenesis in Cr(VI)-induced liver toxicity is still unclear. We demonstrated in the present study that Cr(VI) triggered mitochondrial biogenesis dysfunction-associated apoptosis, and CLU delayed Cr(VI)-induced apoptosis by enhancing mitochondrial biogenesis. Signal transducer and activator of transcription 3 (STAT3) was down-regulated in Cr(VI)-induced apoptosis, and CLU may regulate STAT3 via protein kinase B (PKB/AKT) in Cr(VI)-exposed hepatocytes. We used the STAT3 inhibitor C188-9 and the AKT inhibitor Uprosertib to eliminate the anti-apoptotic effect of CLU, and found that CLU inhibited Cr(VI)-induced apoptosis by up-regulating AKT/STAT3 signal. Based on the fact that both AKT and STAT3 are closely related to mitochondrial biogenesis and mitochondrial pathway-associated apoptosis, this study is the first time to link CLU, STAT3, AKT and mitochondrial biogenesis function after Cr(VI) exposure, to further enrich the experimental basis of Cr(VI)-induced hepatotoxicity, clarify the molecular mechanism of CLU helping cells to escape apoptosis, and also suggest that new ways can be sought to prevent and treat Cr(VI)-induced hepatotoxicity by regulating mitochondrial biosynthesis.