PMID- 32863955 OWN - NLM STAT- MEDLINE DCOM- 20210525 LR - 20210525 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 10 IP - 21 DP - 2020 TI - Fibrinogen-like protein 2 aggravates nonalcoholic steatohepatitis via interaction with TLR4, eliciting inflammation in macrophages and inducing hepatic lipid metabolism disorder. PG - 9702-9720 LID - 10.7150/thno.44297 [doi] AB - 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-kappaB, 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-kappaB, 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. CI - (c) The author(s). FAU - Hu, Junjian AU - Hu J AD - Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Wang, Hongwu AU - Wang H AD - Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Li, Xitang AU - Li X AD - Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Liu, Yonggang AU - Liu Y AD - Tianjin Second People's Hospital and Tianjin Institute of Hepatology, Tianjin, China. FAU - Mi, Yuqiang AU - Mi Y AD - Tianjin Second People's Hospital and Tianjin Institute of Hepatology, Tianjin, China. FAU - Kong, Hongyan AU - Kong H AD - Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Xi, Dong AU - Xi D AD - Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Yan, Weiming AU - Yan W AD - Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Luo, Xiaoping AU - Luo X AD - Department and institute of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Ning, Qin AU - Ning Q AD - Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. FAU - Wang, Xiaojing AU - Wang X AD - Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200801 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - 0 (Cytokines) RN - 0 (FGL2 protein, human) RN - 0 (NF-kappa B) RN - 0 (Reactive Oxygen Species) RN - 0 (TLR4 protein, human) RN - 0 (Toll-Like Receptor 4) RN - 9001-32-5 (Fibrinogen) SB - IM MH - Animals MH - Cytokines/metabolism MH - Diet, High-Fat/adverse effects MH - Fibrinogen/*metabolism MH - Hepatocytes/metabolism MH - Humans MH - Inflammation/*metabolism MH - Lipid Metabolism/physiology MH - Lipid Metabolism Disorders/*metabolism MH - Lipogenesis/physiology MH - Liver/*metabolism MH - Liver Cirrhosis/metabolism MH - Macrophages/*metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - NF-kappa B/metabolism MH - Non-alcoholic Fatty Liver Disease/*metabolism MH - Reactive Oxygen Species/metabolism MH - Signal Transduction/physiology MH - Toll-Like Receptor 4/*metabolism PMC - PMC7449923 OTO - NOTNLM OT - Fibrinogen-like protein 2 OT - Lipid metabolism OT - Macrophage OT - Nonalcoholic steatohepatitis OT - Toll-like receptor 4 COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2020/08/31 06:00 MHDA- 2021/05/26 06:00 PMCR- 2020/01/01 CRDT- 2020/09/01 06:00 PHST- 2020/01/26 00:00 [received] PHST- 2020/07/24 00:00 [accepted] PHST- 2020/09/01 06:00 [entrez] PHST- 2020/08/31 06:00 [pubmed] PHST- 2021/05/26 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - thnov10p9702 [pii] AID - 10.7150/thno.44297 [doi] PST - epublish SO - Theranostics. 2020 Aug 1;10(21):9702-9720. doi: 10.7150/thno.44297. eCollection 2020.