Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
Guangxi Key Laboratory of Immunology and Metabolism for Liver Diseases, Guangxi Medical University, Nanning, 530021, China.
J Gastroenterol. 2023 Sep;58(9):894-907. doi: 10.1007/s00535-023-02002-w. Epub 2023 May 25.
Nonalcoholic steatohepatitis (NASH) is an advanced form of chronic fatty liver disease, which is a driver of hepatocellular carcinoma. However, the roles of the C5aR1 in the NASH remain poorly understood. Here, we aimed to investigate the functions and mechanisms of the C5aR1 on hepatic inflammation and fibrosis in murine NASH model.
Mice were fed a normal chow diet with corn oil (ND + Oil), a Western diet with corn oil (WD + Oil) or a Western diet with carbon tetrachloride (WD + CCl) for 12 weeks. The effects of the C5a-C5aR1 axis on the progression of NASH were analyzed and the underlying mechanisms were explored.
Complement factor C5a was elevated in NASH mice. C5 deficiency reduced hepatic lipid droplet accumulation in the NASH mice. The hepatic expression levels of TNFα, IL-1β and F4/80 were decreased in C5-deficient mice. C5 loss alleviated hepatic fibrosis and downregulated the expression levels of α-SMA and TGFβ1. C5aR1 deletion reduced inflammation and fibrosis in NASH mice. Transcriptional profiling of liver tissues and KEGG pathway analysis revealed that several pathways such as Toll-like receptor signaling, NFκB signaling, TNF signaling, and NOD-like receptor signaling pathway were enriched between C5aR1 deficiency and wild-type mice. Mechanistically, C5aR1 deletion decreased the expression of TLR4 and NLRP3, subsequently regulating macrophage polarization. Moreover, C5aR1 antagonist PMX-53 treatment mitigated the progression of NASH in mice.
Blockade of the C5a-C5aR1 axis reduces hepatic steatosis, inflammation, and fibrosis in NASH mice. Our data suggest that C5aR1 may be a potential target for drug development and therapeutic intervention of NASH.
非酒精性脂肪性肝炎（NASH）是一种慢性脂肪性肝病的晚期形式，是肝细胞癌的驱动因素。然而，C5aR1 在 NASH 中的作用仍知之甚少。在这里，我们旨在研究 C5aR1 在小鼠 NASH 模型中对肝炎症和纤维化的作用和机制。
将小鼠分别用玉米油（ND+Oil）喂养正常饲料、玉米油（WD+Oil）喂养西方饮食或四氯化碳（WD+CCl）喂养西方饮食 12 周。分析 C5a-C5aR1 轴对 NASH 进展的影响，并探讨其潜在机制。
NASH 小鼠补体因子 C5 升高。C5 缺乏减少了 NASH 小鼠肝内脂质滴的积累。TNFα、IL-1β 和 F4/80 的肝表达水平在 C5 缺陷小鼠中降低。C5 缺失减轻了肝纤维化并下调了α-SMA 和 TGFβ1 的表达水平。C5aR1 缺失减少了 NASH 小鼠的炎症和纤维化。肝脏组织的转录谱和 KEGG 途径分析显示，在 C5aR1 缺失和野生型小鼠之间，一些途径如 Toll 样受体信号、NFκB 信号、TNF 信号和 NOD 样受体信号途径富集。在机制上，C5aR1 缺失降低了 TLR4 和 NLRP3 的表达，进而调节巨噬细胞极化。此外，C5aR1 拮抗剂 PMX-53 治疗减轻了小鼠 NASH 的进展。
阻断 C5a-C5aR1 轴可减少 NASH 小鼠的肝脂肪变性、炎症和纤维化。我们的数据表明，C5aR1 可能是 NASH 药物开发和治疗干预的潜在靶点。
