Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis

Aberrant hepatocyte Notch activity is critical to the development of nonalcoholic steatohepatitis (NASH)–induced liver fibrosis, but mechanisms underlying Notch reactivation in developed liver are unclear. Here, we identified that increased expression of the Notch ligand Jagged1 (JAG1) tracked with Notch activation and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in human liver biopsy specimens and mouse NASH models. The increase in Jag1 was mediated by hepatocyte Toll-like receptor 4 (TLR4)–nuclear factor κB (NF-κB) signaling in pericentral hepatocytes. Hepatocyte-specific Jag1 overexpression exacerbated fibrosis in mice fed a high-fat diet or a NASH-provoking diet rich in palmitate, cholesterol, and sucrose and reversed the protection afforded by hepatocyte-specific TLR4 deletion, whereas hepatocyte-specific Jag1 knockout mice were protected from NASH-induced liver fibrosis. To test therapeutic potential of this biology, we designed a Jag1-directed antisense oligonucleotide (ASO) and a hepatocyte-specific N-acetylgalactosamine (GalNAc)–modified siRNA, both of which reduced NASH diet–induced liver fibrosis in mice. Overall, these data demonstrate that increased hepatocyte Jagged1 is the proximal hit for Notch-induced liver fibrosis in mice and suggest translational potential of Jagged1 inhibitors in patients with NASH.

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Alternate-day fasting protects the livers of mice against high-fat diet–induced inflammation associated with the suppression of Toll-like receptor 4/nuclear factor κB signaling

Nutrition Research ◽

10.1016/j.nutres.2016.02.001 ◽

2016 ◽

Vol 36 (6) ◽

pp. 586-593 ◽

Cited By ~ 18

Author(s):

Wanwei Yang ◽

Meng Cao ◽

Xiaodong Mao ◽

Xiao Wei ◽

Xingjia Li ◽

...

Keyword(s):

High Fat Diet ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Toll Like Receptor ◽

High Fat ◽

Toll Like Receptor 4 ◽

Alternate Day Fasting

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Palmitic acid induces guanylin gene expression through the Toll-like receptor 4/nuclear factor-κB pathway in rat macrophages

AJP Cell Physiology ◽

10.1152/ajpcell.00081.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. C1239-C1246

Author(s):

Sayaka Akieda-Asai ◽

Hao Ma ◽

Yukari Date

Keyword(s):

Gene Expression ◽

Palmitic Acid ◽

Gene Transcription ◽

Proinflammatory Cytokines ◽

High Fat Diet ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Toll Like Receptor ◽

High Fat ◽

Toll Like Receptor 4

Recently, we showed that double-transgenic rats overexpressing guanylin (Gn), a bioactive peptide, and its receptor, guanylyl cyclase-C (GC-C), specifically in macrophages demonstrate an antiobesity phenotype and low-expression levels of proinflammatory cytokines in the mesenteric fat even when fed a high-fat diet. Here, we examined the levels and mechanism of Gn and GC-C transcription following saturated fatty acid and lipopolysaccharide (LPS), an activator of Toll-like receptor 4 (TLR4), exposure by using the NR8383 macrophage cell line. In addition, the levels of guanylin and cGMP were increased by addition of either palmitic acid or LPS. Next, we investigated the interaction of the gene transcription and nuclear factor-κB (NF-κB) by using an NF-κB inhibitor and chromatin immunoprecipitation assay. We showed that palmitic acid induced Gn gene expression via TLR4 and NF-κB. Moreover, we demonstrated that NF-κB binding to the Gn promoter was responsible for the induction of gene transcription by palmitic acid or LPS. Our results indicate that saturated fatty acids such as palmitic acid activate Gn gene expression via the NF-κB pathway, raising the possibility that the activated Gn-GC-C system may contribute to the inhibition of high-fat diet-induced proinflammatory cytokines in macrophages.

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Tanshinone IIA attenuates elastase-induced AAA in rats via inhibition of MyD88-dependent TLR-4 signaling

VASA ◽

10.1024/0301-1526/a000326 ◽

2014 ◽

Vol 43 (1) ◽

pp. 39-46 ◽

Cited By ~ 16

Author(s):

Tao Shang ◽

Feng Ran ◽

Qian Qiao ◽

Zhao Liu ◽

Chang-Jian Liu

Keyword(s):

Nuclear Factor Κb ◽

Tanshinone Iia ◽

Myeloid Differentiation ◽

Aortic Tissue ◽

Toll Like Receptor ◽

Sprague Dawley ◽

Toll Like Receptor 4 ◽

Tissue Samples ◽

Myeloid Differentiation Factor ◽

And Control

Background: The purpose of this study was to determine whether myeloid differentiation factor88-dependent Toll-Like Receptor-4 (TLR-4) signaling contributed to the inhibition of abdominal aortic aneurysm (AAA) by Tanshinone IIA (Tan IIA). Materials and methods: Male Sprague-Dawley rats (n = 12 / group) were randomly distributed into three groups: Tan IIA, control, and sham. The rats from Tan IIA and control groups under-went intra-aortic elastase perfusion to induce AAAs, and those in the sham group were perfused with saline. Only the Tan IIA group received Tan IIA (2 mg / rat / d). Aortic tissue samples were harvested at 24 d after perfusion and evaluated using reverse transcriptase-polymerase chain reaction, Western blot, immunohistochemistry and immunofluorescence. Results: The over-expression of Toll-Like Receptor-4 (TLR-4), Myeloid Differentiation factor 88 (MyD88), Phosphorylated Nuclear Factor κB (pNF-κB) and Phosphorylated IκBα (pIκBα) induced by elastase perfusion were significantly decreased by Tan IIA treatment. Conclusions: Tan IIA attenuates elastase-induced AAA in rats possibly via the inhibition of MyD88-dependent TLR-4 signaling, which may be one potential explanation of why Tan IIA inhibits AAA development through multiple effects.

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Hepatic stellate cells specific liposomes with the Toll‐like receptor 4 shRNA attenuates liver fibrosis

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.16209 ◽

2020 ◽

Author(s):

Yuwei Zhang ◽

Yang Li ◽

Tong Mu ◽

Nanwei Tong ◽

Ping Cheng

Keyword(s):

Liver Fibrosis ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Toll Like Receptor ◽

Toll Like Receptor 4

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CD4+CD25+Foxp3+ regulatory T cells regulate immune balance in unexplained recurrent spontaneous abortion via the Toll-like receptor 4/nuclear factor-κB pathway

Journal of International Medical Research ◽

10.1177/0300060520980940 ◽

2020 ◽

Vol 48 (12) ◽

pp. 030006052098094

Author(s):

Shuang Qin ◽

Li Li ◽

Jia Liu ◽

Jinrui Zhang ◽

Qing Xiao ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Inflammatory Response ◽

Mouse Model ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Unexplained Recurrent Spontaneous Abortion ◽

Tlr4 Antagonist

Objective The present study aimed to evaluate the effects of cluster of differentiation (CD)4+CD25+ forkhead box p3 (Foxp3)+ regulatory T cells (Tregs) on unexplained recurrent spontaneous abortion (URSA) and the associated mechanisms. Methods The proportion of CD4+CD25+Foxp3+ Tregs and inflammatory cytokine concentrations in the peripheral blood of women with URSA were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively. CBA/JxDBA/2J mating was used to establish an abortion-prone mouse model and the model mice were treated with the Toll-like receptor 4 (TLR4) antagonist E5564 and the TLR4 agonist lipopolysaccharide. Results The proportion of CD4+CD25+Foxp3+ Tregs was decreased and the inflammatory response was increased in women with URSA. In the abortion-prone mouse model, E5564 significantly increased the proportion of CD4+CD25+Foxp3+ Tregs, decreased the inflammatory response, and increased Foxp3 mRNA and protein expression. Lipopolysaccharide had adverse effects on the abortion-prone model. Conclusions These data suggest that CD4+CD25+Foxp3+ Tregs regulate immune homeostasis in URSA via the TLR4/nuclear factor-κB pathway, and that the TLR4 antagonist E5564 may be a novel and potential drug for treating URSA.

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