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Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis…
Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis Concept Map
Overview of TLRs and TLR4
Toll-like Receptor 4 (TLR4) is a pattern recognition receptor that is crucial for both innate and adaptive immunity
It functions by recognizing specific molecular patterns associated with pathogens and cellular damage
Ligands
TLR4 can be activated by two main types of molecules:
Endogenous Ligands (DAMPs [Damage Associated Molecular Patterns])
lipopolysaccharide (LPS)
Exogenous Ligands (PAMPs [Pathogen Associated Molecular Patterns])
Signaling Pathways
MyD88-independent pathway
MyD88-dependent pathway
Role of TLR4 in Liver Cells and Disease
Key Liver Cells Involved:
Hepatic Stellate Cells (HSCs)
Kupffer Cells (KCs)
Contribution to Liver Diseases:
Non-alcoholic Fatty Liver Disease (NAFLD)
Viral Hepatitis
Alcoholic Liver Disease
TLR4 and Hepatic Fibrogenesis
Mechanism
NF-κB suppresses BAMBI expression
A key mechanism involves a protein called BAMBI (TGF-β pseudoreceptor)
Genetic Evidence
Studies have identified single nucleotide polymorphisms (SNPs), or common genetic variations, in the TLR4 gene
Genetic variants are associated with a significantly slower progression of fibrosis and a lower risk of developing cirrhosis in patients with chronic hepatitis C
Therapeutic Potential
TLR4 Represents a promising target receptor for new therapies.
TLR4 Antagonists
Small molecules such as TAK-242 and E5564 that bind to the TLR4 receptor complex and block its activation
Soluble Fusion Proteins
Proteins which are engineered to bind to and neutralize Lipopolysaccharides (LPS) in the bloodstream before it reaches the liver
Guo J, Friedman SL. 2010. Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis. Fibrogenesis & Tissue Repair. 3(1). doi:
https://doi.org/10.1186/1755-1536-3-21
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