ABSTRACT
Mitochondrial oxidative stress has been a crucial mediator in acetaminophen (APAP)-induced hepatotoxicity. MitoQ, an analog of coenzyme Q10, is targeted towards mitochondria and acts as a potent antioxidant. This study aimed to explore the effect of MitoQ on APAP-induced liver injury and its possible mechanisms. To investigate this, CD-1 mice and AML-12 cells were treated with APAP. Hepatic MDA and 4-HNE, two markers of lipid peroxidation (LPO), were elevated as early as 2 h after APAP. Oxidized lipids were rapidly upregulated in APAP-exposed AML-12 cells. Hepatocyte death and mitochondrial ultrastructure alterations were observed in APAP-induced acute liver injury. The in vitro experiments showed that mitochondrial membrane potentials and OXPHOS subunits were downregulated in APAP-exposed hepatocytes. MtROS and oxidized lipids were elevated in APAP-exposed hepatocytes. We discovered that APAP-induced hepatocyte death and liver injury were ameliorated by attenuation of protein nitration and LPO in MitoQ-pretreated mice. Mechanistically, knockdown of GPX4, a key enzyme for LPO defense systems, exacerbated APAP-induced oxidized lipids, but did not influence the protective effect of MitoQ on APAP-induced LPO and hepatocyte death. Whereas knockdown of FSP1, another key enzyme for LPO defense systems, had little effect on APAP-induced lipid oxidation but partially weakened the protection of MitoQ on APAP-induced LPO and hepatocyte death. These results suggest that MitoQ may alleviate APAP-evoked hepatotoxicity by eliminating protein nitration and suppressing hepatic LPO. MitoQ prevents APAP-induced liver injury partially dependent of FSP1 and independent of GPX4.
Subject(s)
Chemical and Drug Induced Liver Injury, Chronic , Chemical and Drug Induced Liver Injury , Leukemia, Myeloid, Acute , Mice , Animals , Acetaminophen/toxicity , Chemical and Drug Induced Liver Injury, Chronic/metabolism , Liver , Hepatocytes , Leukemia, Myeloid, Acute/metabolism , Chemical and Drug Induced Liver Injury/prevention & control , Chemical and Drug Induced Liver Injury/metabolism , Mice, Inbred C57BL , Oxidative StressABSTRACT
Several experiments confirmed that vitamin D3 protected against acetaminophen (APAP)-induced acute liver injury (ALI). This research aimed to evaluate the influence of vitamin D deficiency (VDD) on APAP-induced ALI. In VDD and VDD + APAP groups, mice were fed with VDD diet. In APAP and VDD + APAP groups, mice were intraperitoneally injected with a sublethal dose of APAP (150 mg/kg). A sublethal dose of APAP caused a slight elevation of ALT and AST. Interestingly, APAP-induced elevation of ALT and AST was aggravated in VDD-fed mice. APAP-induced hepatic necrosis was exacerbated in VDD-fed mice. In addition, APAP-induced hepatocyte death, measured using TUNEL assay, was exacerbated in VDD-fed mice. Additional experiment showed that APAP-induced hepatic GSH depletion and lipid peroxidation were exacerbated in VDD-fed mice. Moreover, APAP-induced upregulation of antioxidant genes, such as hepatic heme oxygenase-1 (Ho-1), glutathione peroxidase (Gshpx), superoxide dismutase 1 (Sod1) and catalase enzymes (Cat), was aggravated in VDD-fed mice. Although a sublethal dose of APAP did not cause hepatic inflammation, hepatic proinflammatory cytokines and chemokines, such as Tnf-α, Kc, Mcp-1 and Mip2, were upregulated in VDD-fed mice treated with APAP. These results provide experimental data that VDD exacerbates hepatic oxidative stress and inflammation during APAP-induced ALI.