Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with TLR4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder
单位：[1]Department and institute of infectious diseases,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,China.华中科技大学同济医学院附属同济医院感染病研究所感染科[2]Tianjin Second People’s Hospital and Tianjin Institute of Hepatology, Tianjin, China.[3]Department and institute of Pediatrics,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,China.华中科技大学同济医学院附属同济医院儿科学系儿科教研室
Rationale: The functions of fibrinogen-like protein 2 (fgl2) have been studied in many inflammatory and neoplastic diseases, but the role of fgl2 in nonalcoholic fatty liver disease has not yet been elucidated. In this study, we sought to investigate the role of fgl2 in the pathogenesis of nonalcoholic steatohepatitis (NASH). Methods: Hepatic fgl2 expression was tested in patients with nonalcoholic fatty liver (NAFL) or NASH and controls. Wild-type and fgl2-/- C57BU6 mice were subjected to a methionine/choline-deficient (MCD) diet or a high-fat diet (HFD) to establish NASH models. Bone marrow-derived macrophages (BMDMs) stimulated with LPS or free fatty acids were used for the in vitro study. Results: In both humans and mice with NASH, macrophage accumulation was concomitant with significantly increased fgl2 expression in the liver. Fgl2 deficiency attenuated liver steatosis and inflammation in diet-induced murine models of NASH. In both liver tissues and BMDMs from NASH mice, fgl2 deficiency resulted in reduced levels of proinflammatory cytokines and reactive oxygen species (ROS) compared with levels in wild-type controls. Activation of NF-kappa B, p38-MAPK and NLRP3 inflammasomes was also suppressed upon fgl2 disruption. Moreover, lipogenic genes (Fasn and SREBP-2) were downregulated while lipolytic genes (PPAR and CPT1A) were upregulated in the livers of fgl2-/- NASH mice. Primary hepatocytes incubated with the medium collected from fgl2-/- BMDMs showed less fat deposition than those incubated with WT BMDMs. Furthermore, we discovered that fgl2 combined with TLR4 mediates the activation of the Myd88-dependent signaling pathway, which may contribute to inflammation and lipid metabolism disorders. Conclusions: These data suggest that fgl2 aggravates the progression of NASH through activation of NF-kappa B, p38-MAPK and NLRP3 inflammasomes in macrophages, which consequently induces overproduction of proinflammatory cytokines and lipid metabolism disorders. An interaction of fgl2 and TLR4 may in part contribute to the activation of inflammatory signaling pathways in macrophages.
基金：
This work was supported by the National
Natural Science Foundation of China (NO. 81500452,
81571989, 81974075), the National Science and Technology Major Project (2018ZX10302206-001-010)
and the Innovation Team Development Plan of the
Ministry of Education (IRT_14R20).
第一作者单位：[1]Department and institute of infectious diseases,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,China.
通讯作者：
通讯机构：[1]Department and institute of infectious diseases,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,China.[*1]Department and institute of infectious diseases,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,1095 Jiefang Avenue,Wuhan 430030,Hubei,China
推荐引用方式(GB/T 7714)：
Junjian Hu,Hongwu Wang,Xitang Li,et al.Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with TLR4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder[J].THERANOSTICS.2020,10(21):9702-9720.doi:10.7150/thno.44297.
APA：
Junjian Hu,Hongwu Wang,Xitang Li,Yonggang Liu,Yuqiang Mi...&Xiaojing Wang.(2020).Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with TLR4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder.THERANOSTICS,10,(21)
MLA：
Junjian Hu,et al."Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with TLR4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder".THERANOSTICS 10..21(2020):9702-9720
医学