3,3′,5‐triiodothyronine (T3) is largely generated from thyroxine (T4) by the catalysis of deiodinases in peripheral tissues and proved to participate in the regulation of various cellular process and metabolism. Emerging evidences have indicated that T3 acts as a protective role to prevent organs from oxidative stress and improves cellular antioxidant capacity. However, the potential correlation between the oxidative stress and conversion of T4 to T3 is still unclear. In the present study, the effects of T3 and T4 on redox homeostatis in HepG2 cells was investigated. It revealed that T3 significantly rescued the cell apoptotic death, consistent with an upregulation of cell antioxidant ability and reduction of ROS accumulation while T4 did not. Afterwards, we examined the enzyme activity and mRNA expression of type 1 5′‐deiodianse (DIO1), T3 and rT3 level and found that H2O2 reduced both DIO1 activity and expression in a dose‐dependent manner, with a consequent decline in T3 and rT3 generation, which was restored by alpha‐lipoic acid (LA) significantly. Moreover, the reduced activity of DIO1 was correlated with the activation of inflammatory signaling pathways at the transcription level, which were notably restored by LA. It suggested that oxidative stress may reduce DIO1 activity by an indirect way like upregulating cellular inflammatory responses. All these results indicate that the oxidative stress downregulates the conversion of T4 to T3 through DIO1 function in HepG2 cells.

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