Theranostics 2020; 10(21):9702-9720. doi:10.7150/thno.44297 This issue Cite

Research Paper

Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with TLR4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder

Junjian Hu1, Hongwu Wang1, Xitang Li1, Yonggang Liu2, Yuqiang Mi2, Hongyan Kong1, Dong Xi1, Weiming Yan1, Xiaoping Luo3, Qin Ning1✉, Xiaojing Wang1✉

1. Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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.

Citation:
Hu J, Wang H, Li X, Liu Y, Mi Y, Kong H, Xi D, Yan W, Luo X, Ning Q, Wang X. Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with TLR4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder. Theranostics 2020; 10(21):9702-9720. doi:10.7150/thno.44297. https://www.thno.org/v10p9702.htm
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Abstract

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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-/- C57BL/6 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-κB, 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-κB, 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.

Keywords: Fibrinogen-like protein 2, Nonalcoholic steatohepatitis, Macrophage, Toll-like receptor 4, Lipid metabolism


Citation styles

APA
Hu, J., Wang, H., Li, X., Liu, Y., Mi, Y., Kong, H., Xi, D., Yan, W., Luo, X., Ning, Q., Wang, X. (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), 9702-9720. https://doi.org/10.7150/thno.44297.

ACS
Hu, J.; Wang, H.; Li, X.; Liu, Y.; Mi, Y.; Kong, H.; Xi, D.; Yan, W.; Luo, X.; Ning, Q.; Wang, X. Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with TLR4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder. Theranostics 2020, 10 (21), 9702-9720. DOI: 10.7150/thno.44297.

NLM
Hu J, Wang H, Li X, Liu Y, Mi Y, Kong H, Xi D, Yan W, Luo X, Ning Q, Wang X. Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with TLR4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder. Theranostics 2020; 10(21):9702-9720. doi:10.7150/thno.44297. https://www.thno.org/v10p9702.htm

CSE
Hu J, Wang H, Li X, Liu Y, Mi Y, Kong H, Xi D, Yan W, Luo X, Ning Q, Wang X. 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):9702-9720.

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