Gender Difference on the Effect of Omega-3 Polyunsaturated Fatty Acids on Acetaminophen-Induced Acute Liver Failure
Gender Difference on the Effect of Omega-3 Polyunsaturated Fatty Acids on Acetaminophen-Induced Acute Liver Failure
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Omega-3 多不饱和脂肪酸对对乙酰氨基酚诱发的急性肝衰竭影响的性别差异
DOI：
10.1155/2020/8096847
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发表时间：
2020
影响因子：
--
通讯作者：
Zuo Daming
中科院分区：
文献类型：
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作者：
Liu Yunzhi;Chen Yu;Xie Xinghuan;Yin Aiping;Yin Yue;Liu Yan;Dong Lijun;Zhu Zhengyumeng;Zhou Jia;Zeng Qingchun;Lu Xiao;Chen Zhengliang;Wen Kun;Zuo Daming
对乙酰氨基酚（APAP）毒性是药物性肝衰竭的主要原因，与线粒体功能障碍和氧化损伤密切相关。临床试验和动物模型研究表明，omega-3多不饱和脂肪酸（n-3 PUFAs）影响各种类型肝损伤的进展。有趣的是，n-3 PUFAs对人类健康的性别依赖性影响也已被充分记录。然而，目前尚不清楚补充n-3 PUFAs是否会调节apap诱导的肝衰竭的发病机制，并具有性别特异性。我们的研究结果表明，内源性和外源性n-3 PUFAs均显著加重了雄性小鼠apap诱导的肝损伤，而雌性小鼠则相反。体内和体外研究表明，雌激素对n-3 PUFAs对APAP过量的调节存在性别差异。我们发现n-3 pufa介导的肝氧化应激反应和APAP攻击后的自噬调节在雄性和雌性小鼠中是不同的。此外，我们提供的证据表明β-catenin信号激活负责n-3 PUFAs对APAP肝毒性的性别依赖性调节。总之，这些发现表明补充n-3 PUFAs对APAP肝毒性的影响存在性别差异，可能在药物性肝损伤的临床管理中具有深远的意义。
Acetaminophen (APAP) toxicity is the leading cause of drug-induced liver failure, which is closely related to mitochondrial dysfunction and oxidative damage. Studies in clinical trials and in animal models have shown that omega-3 polyunsaturated fatty acids (n-3 PUFAs) affect the progression of various types of liver damage. Interestingly, the sex-dependent effect of n-3 PUFAs on human health has also been well documented. However, it is unknown whether supplementation of n-3 PUFAs modulates the pathogenesis of APAP-induced liver failure with sex-specificity. Our results showed that both endogenous and exogenous n-3 PUFAs significantly aggravated the APAP-induced liver injury in male mice, whereas the opposite effects were observed in females. In vivo and in vitro studies demonstrated that estrogen contributes to the gender difference in the regulation of n-3 PUFAs on APAP overdose. We found that n-3 PUFA-mediated regulation of hepatic oxidative stress response and autophagy upon APAP challenge is distinct between male and female mice. Moreover, we provided evidence that β-catenin signaling activation is responsible for the sex-dependent regulation of APAP hepatotoxicity by n-3 PUFAs. Together, these findings indicated that supplementation with n-3 PUFAs displays sex-differential effect on APAP hepatotoxicity and could have profound significance in the clinical management for drug-induced liver injury.