<i>TLR4</i> Gene Polymorphism in Patients with Nonalcoholic Fatty Liver Disease in Comparison to Healthy Controls

Kızıltaş, Şafak; Ata, Pinar; Çolak, Yaşar; Mesçi, Banu; Şenateş, Ebubekir; Enç, Feruze Yılmaz; Ulasoglu, Celal; Tuncer, İlyas; Oğuz, Aytekin

doi:10.1089/met.2013.0120

Cited by 36 publications

(28 citation statements)

References 35 publications

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“…TLR4 gene polymorphism rs10759932 is found to be associated with lifetime cigarette smoking in bipolar disorder [414]. TLR4 codon 299 heterozygous gene mutation (Asp299Gly) is shown to be protective against nonalcoholic fatty liver disease (NAFLD) in humans [415].…”

Section: Tlr Polymorphism In Humans and Their Disease Associationmentioning

confidence: 99%

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

Kumar

2018

International Immunopharmacology

506

346

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The immune system is a very diverse system of the host that evolved during evolution to cope with various pathogens present in the vicinity of environmental surroundings inhabited by multicellular organisms ranging from achordates to chordates (including humans). For example, cells of immune system express various pattern recognition receptors (PRRs) that detect danger via recognizing specific pathogen-associated molecular patterns (PAMPs) and mount a specific immune response. Toll-like receptors (TLRs) are one of these PRRs expressed by various immune cells. However, they were first discovered in the Drosophila melanogaster (common fruit fly) as genes/proteins important in embryonic development and dorso-ventral body patterning/polarity. Till date, 13 different types of TLRs (TLR1-TLR13) have been discovered and described in mammals since the first discovery of TLR4 in humans in late 1997. This discovery of TLR4 in humans revolutionized the field of innate immunity and thus the immunology and host-pathogen interaction. Since then TLRs are found to be expressed on various immune cells and have been targeted for therapeutic drug development for various infectious and inflammatory diseases including cancer. Even, Single nucleotide polymorphisms (SNPs) among various TLR genes have been identified among the different human population and their association with susceptibility/resistance to certain infections and other inflammatory diseases. Thus, in the present review the current and future importance of TLRs in immunity, their pattern of expression among various immune cells along with TLR based therapeutic approach is reviewed.

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Section: Tlr Polymorphism In Humans and Their Disease Associationmentioning

confidence: 99%

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

Kumar

2018

International Immunopharmacology

506

346

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“…Hepatic TLR4 expression was further proved to be up-regulated in a large cohort of NASH patients when compared with NAFL patients, and this seems to occur in a setting of increased plasma endotoxin and fatty acids [135]. An importance of TLR4 signaling was further suggested by the study reporting that TLR4 codon 299 heterozygous gene mutation (Asp299Gly) was significantly lower in the NAFLD than in the control subjects [136].…”

Section: Intestinal Permeability Endotoxemia and Bacterial Translocamentioning

confidence: 95%

Role of Gut Dysbiosis in Liver Diseases: What Have We Learned So Far?

Fukui

2019

Diseases

101

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Accumulating evidence supports that gut dysbiosis may relate to various liver diseases. Alcoholics with high intestinal permeability had a decrease in the abundance of Ruminnococcus. Intestinal dysmotility, increased gastric pH, and altered immune responses in addition to environmental and genetic factors are likely to cause alcohol-associated gut microbial changes. Alcohol-induced dysbiosis may be associated with gut barrier dysfunction, as microbiota and their products modulate barrier function by affecting epithelial pro-inflammatory responses and mucosal repair functions. High levels of plasma endotoxin are detected in alcoholics, in moderate fatty liver to advanced cirrhosis. Decreased abundance of Faecalibacterium prausnitzii, an anti-inflammatory commensal, stimulating IL-10 secretion and inhibiting IL-12 and interferon-γ expression. Proteobacteria, Enterobacteriaceae, and Escherichia were reported to be increased in NAFLD (nonalcoholic fatty liver disease) patients. Increased abundance of fecal Escherichia to elevated blood alcohol levels in these patients and gut microbiota enriched in alcohol-producing bacteria produce more alcohol (alcohol hypothesis). Some undetermined pathological sequences related to gut dysbiosis may facilitate energy-producing and proinflammatory conditions for the progression of NAFLD. A shortage of autochthonous non-pathogenic bacteria and an overgrowth of potentially pathogenic bacteria are common findings in cirrhotic patients. The ratio of the amounts of beneficial autochthonous taxa (Lachnospiraceae + Ruminococaceae + Veillonellaceae + Clostridiales Incertae Sedis XIV) to those of potentially pathogenic taxa (Enterobacteriaceae + Bacteroidaceae) was low in those with early death and organ failure. Cirrhotic patients with decreased microbial diversity before liver transplantation were more likely to develop post-transplant infections and cognitive impairment related to residual dysbiosis. Patients with PSC had marked reduction of bacterial diversity. Enterococcus and Lactobacillus were increased in PSC patients (without liver cirrhosis.) Treatment-naive PBC patients were associated with altered composition and function of gut microbiota, as well as a lower level of diversity. As serum anti-gp210 antibody has been considered as an index of disease progression, relatively lower species richness and lower abundance of Faecalibacterium spp. in gp210-positive patients are interesting. The dysbiosis-induced altered bacterial metabolites such as a hepatocarcinogenesis promotor DCA, together with a leaky gut and bacterial translocation. Gut protective Akkermansia and butyrate-producing genera were decreased, while genera producing-lipopolysaccharide were increased in early hepatocellular carcinoma (HCC) patients.

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“…Our results are in accordance with a study by Day et al[13], in which biopsy-proven patients with NAFLD were genotyped for Asp299Gly single nucleotide polymorphism (SNP) in the TLR4 gene and no association was found between the susceptibility of NASH and the Asp299Gly TLR4 SNP. A recent study by Kiziltas et al[41] demonstrated that subjects with a heterozygous mutation in genotype 299 (Asp299Gly) were significantly lower in the NAFLD group than in the control group. The authors concluded that this mutation may have had a protective role against the genesis of NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphism inCD14gene, a co-receptor of TLR4 associated with non-alcoholic fatty liver disease

Kapil¹,

Duseja²,

Sharma³

et al. 2016

WJG

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AIMTo evaluate the pathogenic role of toll-like receptor (TLR) gene polymorphisms in patients with non-alcoholic fatty liver disease (NAFLD).METHODSTwo hundred and fifty subjects (NAFLD = 200, healthy volunteers = 50) underwent polymerase chain reaction and restriction fragment length polymorphism to assess one polymorphism in the toll-like receptor 2 (TLR2) gene (A753G), two polymorphisms in the TLR4 gene (TLR4 Asp299Gly and Thr399Ile allele), and two polymorphisms in the cluster of differentiation 14 (CD14) (C-159T and C-550T) gene, a co-receptor of TLR4. Association of TLR gene polymorphisms with NAFLD and its severity was evaluated by genetic models of association.RESULTSOn both multiplicative and recessive models of gene polymorphism association, there was significant association of CD14 C (-159) T polymorphism with NAFLD; patients with TT genotype had a 2.6 fold increased risk of developing NAFLD in comparison to CC genotype. There was no association of TLR2 Arg753Gln, TLR4 Asp299Gly, Thr399Ile, and CD14 C (-550) T polymorphisms with NAFLD. None of the TLR gene polymorphisms had an association with histological severity of NAFLD.CONCLUSIONPatients with CD14 C (-159) T gene polymorphism, a co-receptor of TLR4, have an increased risk of NAFLD development.

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TLR4 Gene Polymorphism in Patients with Nonalcoholic Fatty Liver Disease in Comparison to Healthy Controls

Cited by 36 publications

References 35 publications

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

Toll-like receptors in immunity and inflammatory diseases: Past, present, and future

Role of Gut Dysbiosis in Liver Diseases: What Have We Learned So Far?

Genetic polymorphism inCD14gene, a co-receptor of TLR4 associated with non-alcoholic fatty liver disease

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