State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China; Department of Medicine, University of Hong Kong, Hong Kong, China; Department of Pharmacology & Pharmacy, University of Hong Kong, Hong Kong, China.
Hepatology. 2014 Sep;60(3):977-89. doi: 10.1002/hep.27060. Epub 2014 Jul 25.
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.
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.
醋氨酚（APAP）过量是全球导致药物性肝毒性和急性肝衰竭的主要原因，但它的发病机制仍不完全清楚。成纤维细胞生长因子 21（FGF21）是一种由肝细胞分泌的激素，对葡萄糖和脂质代谢具有多种作用。本研究旨在探讨 FGF21 在小鼠 APAP 诱导的肝毒性中的病理生理作用。在 APAP 过量的情况下，小鼠肝脏中 FGF21 的表达和循环水平早在 3 小时前就明显增加，早于丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）等肝损伤标志物的升高。与野生型（WT）同窝仔相比，FGF21 基因敲除（KO）小鼠的 APAP 诱导的肝损伤和死亡率明显加重，同时伴有氧化应激增加和抗氧化能力受损。相比之下，重组 FGF21 的补充在很大程度上逆转了 FGF21 KO 小鼠的 APAP 诱导的肝氧化应激和肝损伤。在机制上，FGF21 诱导了肝过氧化物酶体增殖物激活受体共激活物蛋白-1α（PGC-1α）的表达，从而增加了核因子红细胞 2 相关因子 2（Nrf2）的核含量，并随后上调了几个抗氧化基因。重组 FGF21 对 Nrf2 和抗氧化基因的上调以及缓解 APAP 诱导的氧化应激和肝损伤的有益作用，在很大程度上被肝 PGC-1α 表达的腺病毒介导的敲低所消除，而 PGC-1α 的过表达足以抵消 FGF21 KO 小鼠对 APAP 诱导的肝毒性的易感性增加。
APAP 过量引起的 FGF21 的明显升高可能代表了一种代偿机制，通过增强肝脏中 PGC-1α/Nrf2 介导的抗氧化能力来防止药物性肝毒性。
