Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200001, China.
Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, 350025, China.
Int J Biol Sci. 2022 May 29;18(9):3800-3817. doi: 10.7150/ijbs.71781. eCollection 2022.
: Acetaminophen (APAP)-induced liver injury (AILI) is a common cause of drug-induced liver injury (DILI). The mechanism underlying protection in AILI or DILI remains to be elucidated, and the role of early growth response 1 (Egr1) in AILI and potential mechanisms remain to be known. : The role of Egr1 was studied both and . Liver-specific -knockout () mice and those overexpressing Egr1 via tail vein injection of Egr1-expressing adenovirus (Ad-Egr1) were utilized with AILI. Chromatin immunoprecipitation-sequencing, RNA-sequencing, seahorse XF analysis, and targeted fatty acid analysis were performed. EGR1 levels were also studied in liver tissues and serum samples from AILI/DILI patients. In this study, we have demonstrated that Egr1 was upregulated in AILI models and . liver-specific knockout aggravated AILI; however, Ad-Egr1 treatment ameliorated this. Mechanistically, Egr1 deficiency inhibited, whereas overexpression promoted, mitochondrial respiratory function and fatty acid β-oxidation (FAO) activity in AILI. Egr1 transcriptionally upregulated FAO-related genes in hepatocytes. Notably, the knockdown of (), a key gene involved in FAO, diminished this protective effect of Egr1. Clinically, EGR1 was markedly increased in liver tissues from AILI patients. Interestingly, EGR1 levels of liver tissues and serum samples were also obviously higher in idiosyncratic DILI patients. Egr1 confers adaptive protection in AILI, mediated via the transcriptional upregulation of Acaa2, which improves mitochondrial FAO, and might be a potential biomarker and novel therapeutic target for AILI.
对乙酰氨基酚（APAP）诱导的肝损伤（AILI）是药物性肝损伤（DILI）的常见原因。AILI 或 DILI 中保护作用的机制仍有待阐明，早期生长反应 1（Egr1）在 AILI 中的作用及其潜在机制仍有待了解。
本研究分别在和中研究了 Egr1 的作用。利用肝特异性 -敲除（）小鼠和尾静脉注射 Egr1 表达腺病毒（Ad-Egr1）过表达 Egr1 的小鼠建立 AILI 模型。进行染色质免疫沉淀测序、RNA 测序、 Seahorse XF 分析和靶向脂肪酸分析。还研究了 AILI/DILI 患者肝组织和血清样本中的 EGR1 水平。
在这项研究中，我们已经证明 Egr1 在 AILI 模型中上调。肝特异性缺失加剧了 AILI；然而，Ad-Egr1 治疗改善了这种情况。从机制上讲，Egr1 缺乏抑制，而过表达促进 AILI 中的线粒体呼吸功能和脂肪酸β-氧化（FAO）活性。Egr1 在肝细胞中转录上调 FAO 相关基因。值得注意的是，关键基因（）的敲低削弱了 Egr1 的这种保护作用。临床上，AILI 患者肝组织中 EGR1 明显增加。有趣的是，特发性 DILI 患者肝组织和血清样本中的 EGR1 水平也明显升高。
Egr1 通过转录上调 Acaca2 赋予 AILI 适应性保护，改善线粒体 FAO，可能是 AILI 的潜在生物标志物和新型治疗靶点。
