Jiang Peng, Liu Zhenghong, Fang Tingyu, Zhang Zhidan, Zhang Yu, Wang Dongdong, Little Peter J, Xu Suowen, Weng Jianping
Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, China.
Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Basic Clin Pharmacol Toxicol. 2023 Apr;132(4):343-353. doi: 10.1111/bcpt.13834. Epub 2023 Jan 11.
Acetaminophen (APAP)-induced liver injury (AILI) has been recognized as a pivotal contributor to drug-induced liver failure in Western countries, but its molecular mechanism remains poorly understood. Growth differentiation factor 15 (GDF15) is a pleiotropic factor that alleviates non-alcoholic liver steatohepatitis, liver fibrosis and liver injury. The aim of the present study was to examine the possibility whether GDF15 confers protection against AILI. We found that the gene expression of Gdf15 was increased significantly after APAP overdose in mice. Next, the role of Gdf15 in AILI was evaluated by hepatic Gdf15 overexpression (using adeno-associated virus serotype 8), injection with recombinant human GDF15 (rhGDF15) and Gdf15 knockout mice after challenge with APAP. A marked elevation of Gdf15 was observed after AILI. However, there were no significant differences in AILI-related liver injury and JNK phosphorylation after Gdf15 overexpression, rhGDF15 injection or Gdf15 deficiency. Together, we conclude that, despite a noticeable elevation of Gdf15 level after AILI, Gdf15 is dispensable for APAP-induced AILI. Our study further suggests that genomic analysis of mRNA expression after APAP overdose is of limited relevance unless followed up by a functional analysis of candidate genes in vivo.
对乙酰氨基酚（APAP）诱导的肝损伤（AILI）在西方国家已被公认为药物性肝衰竭的关键促成因素，但其分子机制仍知之甚少。生长分化因子15（GDF15）是一种多效性因子，可减轻非酒精性脂肪性肝炎、肝纤维化和肝损伤。本研究的目的是探讨GDF15是否对AILI具有保护作用。我们发现，小鼠APAP过量后，Gdf15的基因表达显著增加。接下来，通过肝脏Gdf15过表达（使用8型腺相关病毒）、注射重组人GDF15（rhGDF15）以及在APAP攻击后使用Gdf15基因敲除小鼠来评估Gdf15在AILI中的作用。AILI后观察到Gdf15明显升高。然而，Gdf15过表达、rhGDF15注射或Gdf15缺乏后，AILI相关的肝损伤和JNK磷酸化没有显著差异。总之，我们得出结论，尽管AILI后Gdf15水平明显升高，但Gdf15对APAP诱导的AILI并非必需。我们的研究进一步表明，除非随后对体内候选基因进行功能分析，否则APAP过量后mRNA表达的基因组分析相关性有限。
