Hepatocyte-Specific Deficiency of BAP31 Amplified Acetaminophen-Induced Hepatotoxicity via Attenuating Nrf2 Signaling Activation in Mice.
Liver-specific deficiency of B-cell receptor-associated protein 31 knockout mice (BAP31-LKO) and the littermates were injected with acetaminophen (APAP), markers of liver injury, and the potential molecular mechanisms were determined. In response to APAP overdose, serum aspartate aminotransferase and alanine aminotransferase levels were increased in BAP31-LKO mice than in wild-type controls, accompanied by enhanced liver necrosis. APAP-induced apoptosis and mortality were increased. Hepatic glutathione was decreased (1.60 ± 0.31 μmol/g tissue in WT mice vs. 0.85 ± 0.14 μmol/g tissue in BAP31-LKO mice at 6 h, p < 0.05), along with reduced glutathione reductase activity and superoxide dismutase; while malondialdehyde was significantly induced (0.41 ± 0.03 nmol/mg tissue in WT mice vs. 0.50 ± 0.05 nmol/mg tissue in BAP31-LKO mice for 6 h, p < 0.05). JNK signaling activation and APAP-induced hepatic inflammation were increased in BAP31-LKO mice. The mechanism research revealed that BAP31-deficiency decreased Nrf2 mRNA stability (half-life of Nrf2 mRNA decreased from ~1.3 h to ~40 min) and miR-223 expression, led to reduced nuclear factor erythroid 2-related factor 2 (Nrf2) signaling activation and antioxidant genes induction. BAP31-deficiency decreased mitochondrial membrane potentials, reduced mitochondria-related genes expression, and resulted in mitochondrial dysfunction in the liver. Conclusions: BAP31-deficiency reduced the antioxidant response and Nrf2 signaling activation via reducing Nrf2 mRNA stabilization, enhanced JNK signaling activation, hepatic inflammation, and apoptosis, amplified APAP-induced hepatotoxicity in mice.
['Zhao|Jie|J|', 'Lv|Xiaotong|X|', 'Huo|Yan|Y|', 'Hu|Xiaodi|X|', 'Li|Xiaochen|X|', 'Sun|Shizhuo|S|', 'Zhao|Xin|X|', 'Kong|Xuewei|X|', 'Xu|Jialin|J|0000-0002-3910-1306']
D000082:Acetaminophen D000818:Animals D056486:Chemical and Drug Induced Liver Injury D005978:Glutathione D008297:Male D008565:Membrane Proteins D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D051267:NF-E2-Related Factor 2 D018384:Oxidative Stress D017382:Reactive Oxygen Species
BAP31 Nrf2 acetaminophen oxidative stress