Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Biochim Biophys Acta Mol Basis Dis. 2023 Oct;1869(7):166810. doi: 10.1016/j.bbadis.2023.166810. Epub 2023 Jul 22.
Non-alcoholic liver disease (NAFLD) is emerging as the leading cause of end-stage liver disease with a serious threat to global health burden. Fatty acid-binding protein 4 (FABP4) is closely associated with metabolic syndromes. We aimed to explore the potential mechanisms of FABP4 in NAFLD progression.
For NAFLD mice, animals were fed with high fat diet (HFD) for 20 weeks. The assays of hematoxylin and eosin, Sirius Red, oil red O staining and immunohistology were performed to evaluate hepatic pathology. Flow cytometric analysis was used to distinguish macrophage subtypes.
Serum FABP4 level was positively correlate with the severity of hepatic steatosis in NAFLD patients. FABP4 expression was mainly distributed in liver sinusoidal endothelial cells (LSECs), which was significantly increased in HFD mice. The level of CXCL10 was positively correlated with FABP4 at mRNA and serum level. FABP4 inhibition resulted in decreased expression of CXCL10. The percentage of M1 macrophage and CXCR3 cells in infiltrated macrophage was increased in liver of HFD mice. Inhibition of FABP4 ameliorated HFD-induced M1 macrophage polarization as well as CXCR3 macrophages recruitment. Recombinant CXCL10 and co-culturing with TMNK-1 stimulated macrophage toward M1 polarization, which could be reversed by CXCR3 inhibitor. Palmitic acid treatment resulted in increased nuclear P65 expression, which could be reversed by inhibiting FABP4. Cxcl10 expression was dramatically suppressed by NF-κB inhibitor.
FABP4 in LSECs may play a pathogenic role in NAFLD course by promoting CXCL10-mediated macrophage M1 polarization and CXCR3 macrophage infiltration via activating NF-κB/p65 signaling.
非酒精性肝病（NAFLD）正在成为终末期肝病的主要原因，对全球健康负担构成严重威胁。脂肪酸结合蛋白 4（FABP4）与代谢综合征密切相关。我们旨在探讨 FABP4 在 NAFLD 进展中的潜在机制。
对于 NAFLD 小鼠，用高脂肪饮食（HFD）喂养 20 周。进行苏木精和伊红、天狼星红、油红 O 染色和免疫组织化学检测，以评估肝组织病理学变化。采用流式细胞术分析来区分巨噬细胞亚型。
血清 FABP4 水平与 NAFLD 患者肝脂肪变性的严重程度呈正相关。FABP4 表达主要分布在肝窦内皮细胞（LSEC），在 HFD 小鼠中显著增加。CXCL10 的水平与 FABP4 在 mRNA 和血清水平上呈正相关。FABP4 抑制导致 CXCL10 的表达降低。在 HFD 小鼠肝脏中，浸润巨噬细胞中 M1 巨噬细胞和 CXCR3 细胞的比例增加。FABP4 抑制可改善 HFD 诱导的 M1 巨噬细胞极化和 CXCR3 巨噬细胞募集。重组 CXCL10 和与 TMNK-1 共培养刺激巨噬细胞向 M1 极化，而 CXCR3 抑制剂可逆转这一过程。棕榈酸处理导致核 P65 表达增加，而抑制 FABP4 可逆转这一过程。NF-κB 抑制剂可显著抑制 Cxcl10 的表达。
LSEC 中的 FABP4 可能通过促进 CXCL10 介导的巨噬细胞 M1 极化和 CXCR3 巨噬细胞浸润，通过激活 NF-κB/p65 信号通路，在 NAFLD 病程中发挥致病作用。
