KLF10 inhibits CYP450 to reduce TAA-induced hepatic injury

초록

Kruppel-Like Factor 10 (KLF10), an important transcription factor for hepatic glucose and lipid metabolism thought to be linked with liver injury and repair. However, it is not clear if KLF10 plays a role in reducing injury or activating repair in TAA-induced liver injury. Also, the molecular mechanism of KLF10 in the liver injury model is largely unknown. Here, we demonstrated that TAA-induced liver toxicity was significantly increased in KLF10 knockout mice. Strikingly, 70% of KLF10-/- mice die within 48 hours after TAA 300 mg/kg/BW treatment that generally known as a safe dose to induce liver injury without notable lethality. Histological analysis of TAA-treated liver of KLF10 knockout mice revealed a significant increase of TUNNEL positive shrunk hepatic nuclei, characteristics of pyknosis, inflammation, and massive hemorrhage. Also, biochemical analysis revealed KLF10 knockout mouse experienced a significant amount of oxidative stresses after TAA treatment evidenced by the increase of malondialdehyde, a well-known oxidative stresses marker, and the decrease of glutathione, the most abundant cellular thiol antioxidant, in TAA-treated KLF10-/- mouse correlated with an increased protein level of iNOS. For the mechanistic understanding of the protective role of KLF10 against TAA-induced liver toxicity, we showed KLF10 negatively regulates CYP450, a key enzyme to convert nontoxic TAA into toxic metabolites TAASO and TASO2 that triggers necrosis and liver injury. Our findings suggested a protective role of KLF10 against TAA-induced liver injury and provided a unique angle to understand the liver injury.