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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1α-mediated antioxidant capacity in mice
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Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1α-mediated antioxidant capacity in mice

机译：成纤维细胞生长因子21通过增强过氧化物酶体增殖物激活的受体共激活蛋白1α介导的小鼠抗氧化能力来保护对乙酰氨基酚诱导的肝毒性

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摘要

Acetaminophen (APAP) overdose is a leading cause of drug-induced hepatotoxicity and acute liver failure worldwide, but its pathophysiology remains incompletely understood. Fibroblast growth factor 21 (FGF21) is a hepatocyte-secreted hormone with pleiotropic effects on glucose and lipid metabolism. This study aimed to investigate the pathophysiological role of FGF21 in APAP-induced hepatotoxicity in mice. In response to APAP overdose, both hepatic expression and circulating levels of FGF21 in mice were dramatically increased as early as 3 hours, prior to elevations of the liver injury markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST). APAP overdose-induced liver damage and mortality in FGF21 knockout (KO) mice were markedly aggravated, which was accompanied by increased oxidative stress and impaired antioxidant capacities as compared to wild-type (WT) littermates. By contrast, replenishment of recombinant FGF21 largely reversed APAP-induced hepatic oxidative stress and liver injury in FGF21 KO mice. Mechanistically, FGF21 induced hepatic expression of peroxisome proliferator-activated receptor coactivator protein-1α (PGC-1α), thereby increasing the nuclear abundance of nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequent up-regulation of several antioxidant genes. The beneficial effects of recombinant FGF21 on up-regulation of Nrf2 and antioxidant genes and alleviation of APAP-induced oxidative stress and liver injury were largely abolished by adenovirus-mediated knockdown of hepatic PGC-1α expression, whereas overexpression of PGC-1α was sufficient to counteract the increased susceptibility of FGF21 KO mice to APAP-induced hepatotoxicity. Conclusion: The marked elevation of FGF21 by APAP overdose may represent a compensatory mechanism to protect against the drug-induced hepatotoxicity, by enhancing PGC-1α/Nrf2-mediated antioxidant capacity in the liver.
机译：对乙酰氨基酚（APAP）过量是全球药物诱导的肝毒性和急性肝功能衰竭的主要原因，但其病理生理学尚不完全清楚。成纤维细胞生长因子21（FGF21）是一种肝细胞分泌的激素，对葡萄糖和脂质代谢具有多效作用。这项研究旨在探讨FGF21在APAP诱导的小鼠肝毒性中的病理生理作用。响应于APAP过量，在肝损伤标志物丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）升高之前，小鼠的肝脏表达和FGF21的循环水平都在3小时内急剧增加。与野生型（WT）同窝幼仔相比，FGF21基因敲除（KO）小鼠中APAP过量导致的肝损伤和死亡率显着加重，伴随着氧化应激的增加和抗氧化能力的降低。相比之下，重组FGF21的补给很大程度上逆转了APAP诱导的FGF21 KO小鼠的肝氧化应激和肝损伤。从机制上讲，FGF21诱导了过氧化物酶体增殖物激活的受体共激活蛋白1α（PGC-1α）的肝表达，从而增加了核因子红系2相关因子2（Nrf2）的核丰度，并随后上调了一些抗氧化剂基因。腺病毒介导的肝PGC-1α表达的敲除大大消除了重组FGF21对Nrf2和抗氧化剂基因上调以及减轻APAP诱导的氧化应激和肝损伤的有益作用，而PGC-1α的过量表达足以抵消了FGF21 KO小鼠对APAP诱导的肝毒性的敏感性增加。结论：过量应用APAP可使FGF21明显升高，这可能是通过增强PGC-1α/ Nrf2介导的肝脏抗氧化能力来预防药物诱导的肝毒性的补偿机制。

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