FABP4 in LSECs promotes CXCL10-mediated macrophage recruitment and M1 polarization during NAFLD progression,Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

当前位置： X-MOL 学术 › BBA Mol. Basis Dis. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

FABP4 in LSECs promotes CXCL10-mediated macrophage recruitment and M1 polarization during NAFLD progression
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 4.2 ) Pub Date : 2023-07-22 , DOI: 10.1016/j.bbadis.2023.166810
Cui Zhou ₁ , Zhenyang Shen ₁ , Bo Shen ₁ , Weiming Dai ₁ , Zhongsang Sun ₁ , Yuecheng Guo ₁ , Xianjun Xu ₁ , Junjun Wang ₁ , Jingyi Lu ₁ , Qingqing Zhang ₁ , Xin Luo ₁ , Ying Qu ₁ , Hui Dong ₁ , Lungen Lu ₁

Affiliation

Background and aims

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.

Materials and methods

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.

Results

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.

Conclusions

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.

中文翻译：

LSEC 中的 FABP4 在 NAFLD 进展过程中促进 CXCL10 介导的巨噬细胞招募和 M1 极化

背景和目标

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。我们的目的是探讨 FABP4 在 NAFLD 进展中的潜在机制。

材料和方法

对于 NAFLD 小鼠，用高脂肪饮食 (HFD) 喂养动物 20 周。通过苏木精和伊红、天狼星红、油红O染色和免疫组织学检测来评估肝脏病理学。流式细胞术分析用于区分巨噬细胞亚型。

结果

NAFLD患者血清FABP4水平与肝脂肪变性严重程度呈正相关。FABP4表达主要分布在肝窦内皮细胞(LSEC)中，在HFD小鼠中显着增加。CXCL10的水平与FABP4的mRNA和血清水平呈正相关。FABP4 抑制导致 CXCL10 表达降低。HFD 小鼠肝脏中浸润巨噬细胞中M1 巨噬细胞和 CXCR3 ⁺细胞的百分比增加。FABP4 的抑制改善了 HFD 诱导的 M1 巨噬细胞极化以及 CXCR3 ⁺巨噬细胞的招募。重组 CXCL10 以及与 TMNK-1 共培养刺激巨噬细胞向 M1 极化，而 CXCR3 抑制剂可以逆转这种极化。棕榈酸处理导致核 P65 表达增加，这可以通过抑制 FABP4 来逆转。NF-κB 抑制剂显着抑制Cxcl10表达。