Low-dose LPS promotes progress of non-alcoholic steatohepatitis by up-regulating TLR4 in macrophages

Objective To investigate the role and underlying mechanisms of lipopolysaccharide (LPS) in the promotion of non-alcoholic steatohepatitis. Methods Wild type B6 (B6.WT) mice aged 6~8 weeks were randomly divided into 3 groups and fed with normal diet (ND), high-fat diet (HFD) and HFD combined LPS inje...

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Autores principales:	YU Yang, FU Xiaoyan, WU Yanhong, XU Hu, DU Xianhong, WU Pei'en
Formato:	article
Lenguaje:	ZH
Publicado:	Editorial Office of Journal of Third Military Medical University 2021
Materias:	non-alcoholic steatohepatitis high-fat diet lipopolysaccharide chemokine inflammatory cytokine toll-like receptor 4 Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/3a3883070ab346f4ac0e4a9697063f9a
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spelling	oai:doaj.org-article:3a3883070ab346f4ac0e4a9697063f9a2021-11-28T10:45:23ZLow-dose LPS promotes progress of non-alcoholic steatohepatitis by up-regulating TLR4 in macrophages10.16016/j.1000-5404.2021051171000-5404https://doaj.org/article/3a3883070ab346f4ac0e4a9697063f9a2021-11-01T00:00:00Zhttp://aammt.tmmu.edu.cn/Upload/rhtml/202105117.htmhttps://doaj.org/toc/1000-5404Objective To investigate the role and underlying mechanisms of lipopolysaccharide (LPS) in the promotion of non-alcoholic steatohepatitis. Methods Wild type B6 (B6.WT) mice aged 6~8 weeks were randomly divided into 3 groups and fed with normal diet (ND), high-fat diet (HFD) and HFD combined LPS injection (HFD+LPS), respectively. LPS (0111∶B4, 1.25 μg/g body weight) was injected intraperitoneally to the mice of the HFD+LPS group once a week, and normal saline of same amount was given to the mice of the other 2 groups. After 10 weeks' feeding, the levels of triglycerides (TG), total cholesterol (TC), alanine aminotransferase (ALT) and aspartate transaminase (AST) in the serum and liver tissue were detected by enzyme based assays. The lipid deposition in the liver was observed by oil red O staining. The levels of IL-1β, TNF-α, CCL5, CCL2 and CCL4 in the serum and liver tissue were measured by ELISA. The mRNA levels of IL-1β, TNF-α, CCL5, CCL2 and CCL4 in the liver tissue were detected by quantitative real time-PCR (RT-qPCR). The pathological changes of liver tissue and inflammatory cell infiltration were detected by HE staining. Infiltration of macrophages and neutrophils, and the expression of TLR4 in the liver tissue was analyzed by immunofluorescence (IF) assay. Proportion of macrophages and neutrophils in the liver was assessed by flow cytometry. Results The serum levels of TG and TC were significantly higher in the HFD group than the ND group (P < 0.05). Their contents in the liver were markedly increased in the HFD+LPS group than the HFD group (P < 0.01). The mice from the HFD+LPS group had more obvious vacuolar degeneration of liver cells, infiltration of inflammatory cells, higher NAS score (P < 0.05) and larger number of infiltrated mononuclear cells (P < 0.01) when compared with the HFD group. IF assay and flow cytometry proved that HFD+LPS treatment induced significantly obvious infiltration of hepatic macrophages and neutrophil accumulation (P < 0.05). ELISA proved that HFD+LPS treatment increased serum levels of IL-1β, TNF-α, CCL5 and CCL2 (P < 0.05), elevated mRNA levels of IL-1β, CCL5 and CCL2 in the liver tissue (P < 0.05). IF revealed that TLR4 showed obvious cell membrane translocation in liver tissue after LPS treatment, and the co localization of TLR4 and macrophages showed that the expression of TLR4 on the surface of macrophages in HFD + LPS group was significantly higher than that in HFD group(P < 0.01). Conclusion LPS mediates intrahepatic infiltration of macrophages and neutrophils and aggravates the process of NASH in mice fed with HFD through upregulating TLR4 expression on macrophages to induce chemokines and inflammatory cytokines.YU YangFU XiaoyanFU XiaoyanWU YanhongXU HuDU XianhongDU Xianhong WU Pei'enEditorial Office of Journal of Third Military Medical Universityarticlenon-alcoholic steatohepatitishigh-fat dietlipopolysaccharidechemokineinflammatory cytokinetoll-like receptor 4Medicine (General)R5-920ZHDi-san junyi daxue xuebao, Vol 43, Iss 22, Pp 2423-2434 (2021)
institution	DOAJ
collection	DOAJ
language	ZH
topic	non-alcoholic steatohepatitis high-fat diet lipopolysaccharide chemokine inflammatory cytokine toll-like receptor 4 Medicine (General) R5-920
spellingShingle	non-alcoholic steatohepatitis high-fat diet lipopolysaccharide chemokine inflammatory cytokine toll-like receptor 4 Medicine (General) R5-920 YU Yang FU Xiaoyan FU Xiaoyan WU Yanhong XU Hu DU Xianhong DU Xianhong WU Pei'en Low-dose LPS promotes progress of non-alcoholic steatohepatitis by up-regulating TLR4 in macrophages
description	Objective To investigate the role and underlying mechanisms of lipopolysaccharide (LPS) in the promotion of non-alcoholic steatohepatitis. Methods Wild type B6 (B6.WT) mice aged 6~8 weeks were randomly divided into 3 groups and fed with normal diet (ND), high-fat diet (HFD) and HFD combined LPS injection (HFD+LPS), respectively. LPS (0111∶B4, 1.25 μg/g body weight) was injected intraperitoneally to the mice of the HFD+LPS group once a week, and normal saline of same amount was given to the mice of the other 2 groups. After 10 weeks' feeding, the levels of triglycerides (TG), total cholesterol (TC), alanine aminotransferase (ALT) and aspartate transaminase (AST) in the serum and liver tissue were detected by enzyme based assays. The lipid deposition in the liver was observed by oil red O staining. The levels of IL-1β, TNF-α, CCL5, CCL2 and CCL4 in the serum and liver tissue were measured by ELISA. The mRNA levels of IL-1β, TNF-α, CCL5, CCL2 and CCL4 in the liver tissue were detected by quantitative real time-PCR (RT-qPCR). The pathological changes of liver tissue and inflammatory cell infiltration were detected by HE staining. Infiltration of macrophages and neutrophils, and the expression of TLR4 in the liver tissue was analyzed by immunofluorescence (IF) assay. Proportion of macrophages and neutrophils in the liver was assessed by flow cytometry. Results The serum levels of TG and TC were significantly higher in the HFD group than the ND group (P < 0.05). Their contents in the liver were markedly increased in the HFD+LPS group than the HFD group (P < 0.01). The mice from the HFD+LPS group had more obvious vacuolar degeneration of liver cells, infiltration of inflammatory cells, higher NAS score (P < 0.05) and larger number of infiltrated mononuclear cells (P < 0.01) when compared with the HFD group. IF assay and flow cytometry proved that HFD+LPS treatment induced significantly obvious infiltration of hepatic macrophages and neutrophil accumulation (P < 0.05). ELISA proved that HFD+LPS treatment increased serum levels of IL-1β, TNF-α, CCL5 and CCL2 (P < 0.05), elevated mRNA levels of IL-1β, CCL5 and CCL2 in the liver tissue (P < 0.05). IF revealed that TLR4 showed obvious cell membrane translocation in liver tissue after LPS treatment, and the co localization of TLR4 and macrophages showed that the expression of TLR4 on the surface of macrophages in HFD + LPS group was significantly higher than that in HFD group(P < 0.01). Conclusion LPS mediates intrahepatic infiltration of macrophages and neutrophils and aggravates the process of NASH in mice fed with HFD through upregulating TLR4 expression on macrophages to induce chemokines and inflammatory cytokines.
format	article
author	YU Yang FU Xiaoyan FU Xiaoyan WU Yanhong XU Hu DU Xianhong DU Xianhong WU Pei'en
author_facet	YU Yang FU Xiaoyan FU Xiaoyan WU Yanhong XU Hu DU Xianhong DU Xianhong WU Pei'en
author_sort	YU Yang
title	Low-dose LPS promotes progress of non-alcoholic steatohepatitis by up-regulating TLR4 in macrophages
title_short	Low-dose LPS promotes progress of non-alcoholic steatohepatitis by up-regulating TLR4 in macrophages
title_full	Low-dose LPS promotes progress of non-alcoholic steatohepatitis by up-regulating TLR4 in macrophages
title_fullStr	Low-dose LPS promotes progress of non-alcoholic steatohepatitis by up-regulating TLR4 in macrophages
title_full_unstemmed	Low-dose LPS promotes progress of non-alcoholic steatohepatitis by up-regulating TLR4 in macrophages
title_sort	low-dose lps promotes progress of non-alcoholic steatohepatitis by up-regulating tlr4 in macrophages
publisher	Editorial Office of Journal of Third Military Medical University
publishDate	2021
url	https://doaj.org/article/3a3883070ab346f4ac0e4a9697063f9a
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_version_	1718408252667985920

Low-dose LPS promotes progress of non-alcoholic steatohepatitis by up-regulating TLR4 in macrophages

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