Emergency Department, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China.
J Gastroenterol. 2024 Apr;59(4):342-356. doi: 10.1007/s00535-024-02082-2. Epub 2024 Feb 24.
Non-alcoholic steatohepatitis (NASH) is a rapidly progressing chronic liver disease of global significance. However, the underlying mechanisms responsible for NASH remain unknown. Indoleamine 2,3-dioxygenase 1 (IDO1) has been recognized as essential factor in immune response and metabolic regulation. Here we aimed to investigate the functions and mechanisms of the IDO1 in macrophages on hepatic lipid deposition and iron metabolism in NASH.
The effect of IDO1 in NASH was evaluated by WT and IDO1 mice model fed with methionine/choline-deficient (MCD) diet in vivo. Macrophages scavenger clodronate liposomes (CL) and overexpressing of IDO1 in macrophages by virus were employed as well. Lipid deposition was assessed through pathological examination and lipid droplet staining, while iron levels were measured using an iron assay kit and western blotting. Primary hepatocytes and bone marrow-derived macrophages were treated with oleic acid/palmitic acid (OA/PA) to assess IDO1 expression via Oil Red O staining and immunofluorescence staining in vitro.
Pathological images demonstrated that the increase of IDO1 exacerbated lipid accumulation in the livers of mice with MCD diet, while reduction of iron accumulation was observed in the liver and the serum of MCD-fed mice. Scavenging of macrophages effectively mitigated both lipid and iron accumulation. In addition, the deficiency of IDO1 in macrophages significantly mitigated lipid accumulation and iron overload in hepatic parenchymal cells. Finally, lentivirus-mediated overexpression of IDO1 in liver macrophages exacerbated hepatic steatosis and iron deposition in NASH.
Our results demonstrated that effective inhibition of IDO1 expression in macrophages in NASH alleviated hepatic parenchymal cell lipid accumulation and iron deposition, which provided new insights for the future treatment of NASH.
非酒精性脂肪性肝炎（NASH）是一种具有全球意义的快速进展性慢性肝脏疾病。然而，导致 NASH 的潜在机制尚不清楚。吲哚胺 2,3-双加氧酶 1（IDO1）已被认为是免疫反应和代谢调节的重要因素。本研究旨在探讨 IDO1 在巨噬细胞中对 NASH 肝内脂质沉积和铁代谢的作用及机制。
采用野生型（WT）和 IDO1 敲除（IDO1-/-）小鼠模型，经蛋氨酸/胆碱缺乏（MCD）饮食喂养，体内评估 IDO1 的作用。此外，还使用巨噬细胞清道夫 clodronate 脂质体（CL）和病毒过表达巨噬细胞中的 IDO1。通过病理检查和脂滴染色评估脂质沉积，通过铁测定试剂盒和 Western blot 检测铁水平。用油酸/棕榈酸（OA/PA）处理原代肝细胞和骨髓来源的巨噬细胞，通过油红 O 染色和免疫荧光染色评估 IDO1 表达。
病理图像表明，MCD 饮食增加 IDO1 可加剧小鼠肝脏脂质蓄积，而 MCD 喂养小鼠肝脏和血清铁蓄积减少。巨噬细胞耗竭可有效减轻脂质和铁蓄积。此外，巨噬细胞中 IDO1 的缺失可显著减轻肝实质细胞的脂质蓄积和铁超负荷。最后，肝巨噬细胞中过表达 IDO1 的慢病毒可加重 NASH 中的肝脂肪变性和铁沉积。
本研究结果表明，NASH 中巨噬细胞中 IDO1 的有效抑制可减轻肝实质细胞的脂质蓄积和铁沉积，为 NASH 的未来治疗提供了新的思路。
