ArticlePloS one2016
TLR4 Deficiency Protects against Hepatic Fibrosis and Diethylnitrosamine-Induced Pre-Carcinogenic Liver Injury in Fibrotic Liver.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 30 citations in OpenAlex.
- The role of cytotoxicity in the process of carcinogenesis.Archives of toxicology · 2026Article
- Persistent interferon signaling and clonal expansion mark early events in DNA methylation damage-induced liver cancer.NAR cancer · 2026Article
- Persistent interferon signaling and clonal expansion mark early events in DNA methylation damage-induced liver cancer.bioRxiv : the preprint server for biology · 2025Article
- The interventional role and mechanism of total flavonoids in lychee seeds on rats with liver fibrosis.Scientific reports · 2025Article
- Synergism between TLR4 and B. infantis in the development of the premature intestine.Pediatric research · 2025Article
- Screening of Multitarget Compounds against Acetaminophen Hepatic Toxicity Using In Silico, In Vitro, and In Vivo Approaches.Molecules (Basel, Switzerland) · 2024Article
- Pathomorphological Manifestations and the Course of the Cervical Cancer Disease Determined by Variations in theDiagnostics (Basel, Switzerland) · 2023Article
- The Role of TLR4 in the Immunotherapy of Hepatocellular Carcinoma: Can We Teach an Old Dog New Tricks?Cancers · 2023Review
- A novel mechanistic approach for the anti-fibrotic potential of rupatadine in rat liver via amendment of PAF/NF-ĸB p65/TGF-β1 and hedgehog/HIF-1α/VEGF trajectories.Inflammopharmacology · 2023Article
- Iron as a therapeutic target in chronic liver disease.World journal of gastroenterology · 2023Review
- Review
- Design and optimisation of a small-molecule TLR2/4 antagonist for anti-tumour therapy.RSC medicinal chemistry · 2021Article
- Hypoxia-Inducible Ubiquitin Specific Peptidase 13 Contributes to Tumor Growth and Metastasis via Enhancing the Toll-Like Receptor 4/Myeloid Differentiation Primary Response Gene 88/Nuclear Factor-κB Pathway in Hepatocellular Carcinoma.Frontiers in cell and developmental biology · 2020Article
- Gut Microbiota, Peroxisome Proliferator-Activated Receptors, and Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2020Review
- Gut-liver axis signaling in portal hypertension.World journal of gastroenterology · 2019Review
- Sparstolonin B (SsnB) attenuates liver fibrosis via a parallel conjugate pathway involving P53-P21 axis, TGF-beta signaling and focal adhesion that is TLR4 dependent.European journal of pharmacology · 2018Article
- Impact of miR-140 Deficiency on Non-Alcoholic Fatty Liver Disease.Molecular nutrition & food research · 2018Article
- Deficiency of pyruvate dehydrogenase kinase 4 sensitizes mouse liver to diethylnitrosamine and arsenic toxicity through inducing apoptosis.Liver research (Beijing, China) · 2018Article
- Therapeutic potential of phages in autoimmune liver diseases.Clinical and experimental immunology · 2018Review
- Low hepcidin in liver fibrosis and cirrhosis; a tale of progressive disorder and a case for a new biochemical marker.Molecular medicine (Cambridge, Mass.) · 2018Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe development of hepatocellular carcinoma (HCC) is a common consequence of advanced liver fibrosis but the interactions between fibrogenesis and carcinogenesis are still poorly understood. Recently it has been shown that HCC promotion depends on Toll-like receptor (TLR) 4. Pre-cancerogenous events can be modelled in mice by the administration of a single dose of diethylnitrosamine (DEN), with HCC formation depending amongst others on interleukin (IL) 6 production. Mice lacking the hepatocanalicular phosphatidylcholine transporter ABCB4 develop liver fibrosis spontaneously, resemble patients with sclerosing cholangitis due to mutations of the orthologous human gene, and represent a valid model to study tumour formation in pre-injured cholestatic liver. The aim of this study was to investigate DEN-induced liver injury in TLR4-deficient mice with biliary fibrosis.
methodsABCB4-deficient mice on the FVB/NJ genetic background were crossed to two distinct genetic backgrounds (TLR4-sufficient C3H/HeN and TLR4-deficient C3H/HeJ) for more than 10 generations. The two congenic knockout and the two corresponding wild-type mouse lines were treated with a single dose of DEN for 48 hours. Phenotypic differences were assessed by measuring hepatic collagen contents, inflammatory markers (ALT, CRP, IL6) as well as hepatic apoptosis (TUNEL) and proliferation (Ki67) rates.
resultsHepatic collagen accumulation is significantly reduced in ABCB4-/-:TLR4-/-double-deficient mice. After DEN challenge, apoptosis, proliferation and inflammatory markers are decreased in TLR4-deficient in comparison to TLR4-sufficient mice. When combining ABCB4 and TLR4 deficiency with DEN treatment, hepatic IL6 expression and proliferation rates are lowest in fibrotic livers from the double-deficient line. Consistent with these effects, selective digestive tract decontamination in ABCB4-/- mice also led to reduced tumor size and number after DEN.
conclusionThis study demonstrates that liver injury upon DEN challenge depends on pre-existing fibrosis and genetic background. The generation of ABCB4-/: TLR4-/- double-deficient mice illustrates that TLR4-deficiency protects against hepatic injury in a preclinical mouse model of chronic liver disease.
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