The role of lipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases

Soares, José; Pimentel‐Nunes, Pedro; Roncon‐Albuquerque, Roberto; Leite‐Moreira, Adelino F.

doi:10.1007/s12072-010-9219-x

Cited by 274 publications

(238 citation statements)

References 85 publications

(126 reference statements)

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“…CCl 4 -induced liver fibrosis activates hepatic stellate cells via TLR4 (19,20), enhanced by signal transduction emanating from the TLR4 complex induced by gut bacterial products and LPS (1). To investigate whether activation of IRF3 in acute CCl 4 liver injury was mediated by the intracellular MyD88-independent TLR4 adaptors TRIF and TRAM), or the kinase TBK1, we first inhibited activity of their downstream kinase, TBK1, by the chemical inhibitor BX795 in vivo.…”

Section: Irf3 Deficiency Attenuates Chronic CCL 4 -Mediated Livermentioning

confidence: 99%

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Iracheta-Vellve

Petrášek

Gyöngyösi

et al. 2016

Journal of Biological Chemistry

132

119

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Edited by Jeffrey PessinFibrosis, driven by inflammation, marks the transition from benign to progressive stages of chronic liver diseases. Although inflammation promotes fibrogenesis, it is not known whether other events, such as hepatocyte death, are required for the development of fibrosis. Interferon regulatory factor 3 (IRF3) regulates hepatocyte apoptosis and production of type I IFNs. In the liver, IRF3 is activated via Toll-like receptor 4 (TLR4) signaling or the endoplasmic reticulum (ER) adapter, stimulator of interferon genes (STING). We hypothesized that IRF3-mediated hepatocyte death is an independent determinant of chemically induced liver fibrogenesis. To test this, we performed acute or chronic CCl 4 administration to WT and IRF3-, Toll/ Interleukin-1R (TIR) domain-containing adapter-inducing interferon-␤ (TRIF)-, TRIF-related adaptor molecule (TRAM)-, and STING-deficient mice. We report that acute CCl 4 administration to WT mice resulted in early ER stress, activation of IRF3, and type I IFNs, followed by hepatocyte apoptosis and liver injury, accompanied by liver fibrosis upon repeated administration of CCl 4 . Deficiency of IRF3 or STING prevented hepatocyte death and fibrosis both in acute or chronic CCl 4 . In contrast, mice deficient in type I IFN receptors or in TLR4 signaling adaptors, TRAM or TRIF, upstream of IRF3, were not protected from hepatocyte death and/or fibrosis, suggesting that the proapoptotic role of IRF3 is independent of TLR signaling in fibrosis. Hepatocyte death is required for liver fibrosis with causal involvement of STING and IRF3. Thus, our results identify that IRF3, by its association with STING in the presence of ER stress, couples hepatocyte apoptosis with liver fibrosis and indicate that innate immune signaling regulates outcomes of liver fibrosis via modulation of hepatocyte death in the liver.

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Section: Irf3 Deficiency Attenuates Chronic CCL 4 -Mediated Livermentioning

confidence: 99%

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Iracheta-Vellve

Petrášek

Gyöngyösi

et al. 2016

Journal of Biological Chemistry

132

119

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“…The contribution of increased intestinal permeability (20), overgrowth of bacteria (15), and elevated serum LPS (31,32) has been shown in patients with NAFLD. Overgrowth of bacteria, in particular gram-negative bacteria, increases the production of hepatotoxic products such as LPS (23).…”

Section: Introductionmentioning

confidence: 99%

“…The disruption of the intestinal integrity increases intestinal permeability, which leads to bacterial translocation, and bacterial endotoxins penetrate into the portal vein, which increases the risk of NAFLD development through the activation of hepatic inflammatory cells (23,33). Bacterial endotoxins are recognized by toll-like receptors (TLRs) on hepatocytes, which recognize several components of microbes and initiate immunologic responses (32). When bacterial LPS signals through TLR4, signaling ultimately activates NF-kB and proinflammatory cytokines (32,34).…”

Section: Introductionmentioning

confidence: 99%

“…Bacterial endotoxins are recognized by toll-like receptors (TLRs) on hepatocytes, which recognize several components of microbes and initiate immunologic responses (32). When bacterial LPS signals through TLR4, signaling ultimately activates NF-kB and proinflammatory cytokines (32,34). Moreover, dysbiosis is associated with reduced synthesis and secretion of fasting-induced adipocyte factor [(FIAF) also known as angiopoietin-like 4] in enterocytes, which results in increased activity of lipoprotein lipase (LPL) and the accumulation of TGs in the liver (35,36).…”

Section: Introductionmentioning

confidence: 99%

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Nonalcoholic Fatty Liver Disease, the Gut Microbiome, and Diet

Mokhtari

Gibson

Hekmatdoost

2017

Advances in Nutrition

138

100

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Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder in the world, yet the pathogenesis of the disease is not well elucidated. Due to the close anatomic and functional association between the intestinal lumen and the liver through the portal system, it is speculated that the gut microbiome may play a pivotal role in the pathogenesis of NAFLD. Furthermore, diet, which can modulate the gut microbiome and several metabolic pathways involved in NAFLD development, shows a potential tripartite relation between the gut, diet, and the liver. In this review, we summarize the current evidence that supports the association between NAFLD, the gut microbiome, and the role of diet. Adv Nutr 2017;8:240-52.

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“…The innate immune system may also be vital to its progression, and the activation of TLR4 appears to be crucial for the progression of the disease sequence of steatosis-steatohepatitis-fi brosis-cirrhosis and, fi nally, hepatocarcinoma, as we previously reviewed (18). It seems that TLR4 signaling is enhanced in chronic liver disease, such as NAFLD (19). Besides, in a human virus induced hepatic infl ammation-fi brosis-cirrhosis sequence, we found an upregulation of TLR2 and TLR4 (20).…”

Section: Introductionmentioning

confidence: 92%

Characterization of liver changes in ZSF1 rats, an animal model of metabolic syndrome

et al. 2017

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A, Pimentel-Nunes P. Characterization of liver changes in ZSF1 rats, an animal model of metabolic syndrome. Rev Esp Enferm Dig 2017;109(7): 491-497. DOI: 10.17235/reed.2017491-497. DOI: 10.17235/reed. .4575/2016 Received: 26-08-201626-08- Accepted: 25-02-2017 Correspondence: Marta Borges-Canha. Department of Physiology and Cardiothoracic Surgery. Faculty of Medicine. University of Porto. Alameda Prof. Hernâni Monteiro. 4200-319 Porto, Portugal e-mail: marta.canha@gmail.com ABSTRACT Background:The non-alcoholic fatty liver disease is the hepatic counterpart of the metabolic syndrome. ZSF1 rats are a metabolic syndrome animal model in which liver changes have not been described yet.Aim: The characterization of liver histological and innate immunity changes in ZSF1 rats.Methods: Five groups of rats were included (n = 7 each group): healthy Wistar-Kyoto control rats (Ctrl), hypertensive ZSF1 lean (Ln), ZSF1 obese rats with a normal diet (Ob), ZSF1 obese rates with a high-fat diet (Ob-HFD), and ZSF1 obese rats with low-intensity exercise training (Ob-Ex). Results: Ob, Ob-HFD and Ob-Ex were significantly heavier than Ln and Ctrl animals. Ob, Ob-HFD and Ob-Ex animals had impaired glucose tolerance and insulin resistance. ZSF1 Ob, Ob-HFD and Ob-Ex presented a higher degree of steatosis (3,5x; p < 0.05) than Ctrl or ZSF1 Ln rats. Steatohepatitis and fibrosis were not observed in any of the groups. No differences in expression were observed between Ctrl, Ln and Ob animals (except for the significantly higher expression of TOLLIP observed in the Ob vs Ln comparison). Ob-HFD and Ob-Ex rats showed increased expression of PPARγ and TOLLIP as compared to other groups. However, both groups also showed increased expression of TLR2 and TLR4. Nevertheless, this did not translate into a differential expression of TNFα or IL-1 in any of the groups.Conclusion: The ZSF1 model is associated with liver steatosis but not with steatohepatitis or a significantly increased expression of innate immunity or inflammation markers.

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The role of lipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases

Cited by 274 publications

References 85 publications

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Endoplasmic Reticulum Stress-induced Hepatocellular Death Pathways Mediate Liver Injury and Fibrosis via Stimulator of Interferon Genes

Nonalcoholic Fatty Liver Disease, the Gut Microbiome, and Diet

Characterization of liver changes in ZSF1 rats, an animal model of metabolic syndrome

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