Acetaminophen-induced liver injury is attenuated in transgenic fat-1 mice endogenously synthesizing long-chain n-3 fatty acids
Acetaminophen-induced liver injury is attenuated in transgenic fat-1 mice endogenously synthesizing long-chain n-3 fatty acids
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DOI：
10.1016/j.bcp.2018.04.019
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发表时间：
2018-08-01
影响因子：
5.8
通讯作者：
Wan, Jim-Bo
中科院分区：
文献类型：
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作者：
Feng, Ruibing;Wang, Yang;Wan, Jim-Bo
对乙酰氨基酚（APAP）过量诱导的肝毒性是药物诱导的肝衰竭的最常见原因，其特征在于氧化应激、线粒体功能障碍和细胞损伤。omega-3多不饱和脂肪酸（n-3 PUFA）在几种肝脏疾病模型中的治疗效果已得到充分证明。然而，n-3 PUFA对APAP肝毒性的影响尚未得到充分解决。本研究以400 mg/kg剂量腹腔注射APAP诱导内源性n-3 PUFA的fat-1转基因小鼠和野生型（WT）同窝小鼠肝损伤，并在注射APAP后0 h、2 h、4 h和6 h处死小鼠取样。APAP过量可引起WT小鼠严重的肝损伤，如血清参数、组织病理学变化和肝细胞凋亡所示，而Fat-1小鼠的肝损伤明显减轻。n-3 PUFA的这些保护作用与通过抑制凋亡信号调节激酶1（ASK 1）/促分裂原活化蛋白激酶激酶4（MKK 4）途径调节JNK活化延长有关。此外，内源性n-3 PUFA的增加减少了APAP处理诱导的肝脏中核因子κ B（NF-κ B）介导的炎症反应。这些结果表明，n-3 PUFA对APAP诱导的急性肝损伤具有有效的保护作用，表明含有n-3 PUFA的n-3膳食补充剂可能是治疗APAP过量诱导的肝毒性的潜在治疗策略。
Acetaminophen (APAP) overdose-induced hepatotoxicity is the most commonly cause of drug-induced liver failure characterized by oxidative stress, mitochondrial dysfunction, and cell damage. Therapeutic efficacy of omega-3 polyunsaturated fatty acids (n-3 PUFA) in several models of liver disease is well documented. However, the impacts of n-3 PUFA on APAP hepatotoxicity are not adequately addressed. In this study, the fat-1 transgenic mice that synthesize endogenous n-3 PUFA and wild type (WT) littermates were injected intraperitoneally with APAP at the dose of 400 mg/kg to induce liver injury, and euthanized at 0h, 2h, 4h and 6h post APAP injection for sampling. APAP overdose caused severe liver injury in WT mice as indicated by serum parameters, histopathological changes and hepatocyte apoptosis, which were remarkably ameliorated in fat-1 mice. These pro tective effects of n-3 PUFA were associated with regulation of the prolonged JNK activation via inhibition of apoptosis signal-regulating kinase 1 (ASKl)/mitogen-activated protein kinase kinase 4 (MKK4) pathway. Additionally, the augment of endogenous n-3 PUFA reduced nuclear factor kappa B (NF-kB) - mediated in flammation response induced by APAP treatment in the liver. These findings indicate that n-3 PUFA has potent protective effects against APAP-induced acute liver injury, suggesting that n-3 dietary supplement with n-3 PUFA may be a potential therapeutic strategy for the treatment of hepatotoxicity induced by APAP overdose.