title: Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice.
abstract: Toll-like receptor 4 (TLR4) and its coreceptor, myeloid differentiation factor-2 (MD-2), are key in recognition of lipopolysaccharide (LPS) and activation of proinflammatory pathways. Here we tested the hypothesis that TLR4 and its coreceptor MD-2 play a central role in nonalcoholic steatohepatitis (NASH) and liver fibrosis in nonalcoholic fatty liver disease. Mice of control genotypes and those deficient in MD-2 or TLR4 [knockout (KO)] received methionine choline-deficient (MCD) or methionine choline-supplemented (MCS) diet. In mice of control genotypes, MCD diet resulted in NASH, liver triglycerides accumulation, and increased thiobarbituric acid reactive substances, a marker of lipid peroxidation, compared with MCS diet. These features of NASH were significantly attenuated in MD-2 KO and TLR4 KO mice. Serum alanine aminotransferase, an indicator of liver injury, was increased in MCD diet-fed genotype controls but was attenuated in MD-2 KO and TLR4 KO mice. Inflammatory activation, indicated by serum TNF-α and nictoinamide adenine dinucleotide phosphate oxidase complex mRNA expression and activation, was significantly lower in MCD diet-fed MD-2 KO and TLR4 KO compared with corresponding genotype control mice. Markers of liver fibrosis [collagen by Sirius red and α-smooth muscle actin (SMA) staining, procollagen-I, transforming growth factor-β1, α-SMA, matrix metalloproteinase-2, and tissue inhibitor of matrix metalloproteinase-1 mRNA] were attenuated in MD-2 and TLR4 KO compared with their control genotype counterparts. In conclusion, our results demonstrate a novel, critical role for LPS recognition complex, including MD-2 and TLR4, through NADPH activation in liver steatosis, and fibrosis in a NASH model in mice.
authors.affiliation: Department of Medicine, University of Massachusetts, Medical School, Worcester, 01605-2324, USA.
authors.forename: Timea
authors.initials: T
authors.lastname: Csak
authors.forename: Arumugam
authors.initials: A
authors.lastname: Velayudham
authors.forename: Istvan
authors.initials: I
authors.lastname: Hritz
authors.forename: Jan
authors.initials: J
authors.lastname: Petrasek
authors.forename: Ivan
authors.initials: I
authors.lastname: Levin
authors.forename: Dora
authors.initials: D
authors.lastname: Lippai
authors.forename: Donna
authors.initials: D
authors.lastname: Catalano
authors.forename: Pranoti
authors.initials: P
authors.lastname: Mandrekar
authors.forename: Angela
authors.initials: A
authors.lastname: Dolganiuc
authors.forename: Evelyn
authors.initials: E
authors.lastname: Kurt-Jones
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000199:Actins / Q000235:genetics; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D003094:Collagen / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D005838:Genotype; D015227:Lipid Peroxidation; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D051218:Lymphocyte Antigen 96 / Q000172:deficiency* / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000199:Actins; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D017392:Thiobarbituric Acid Reactive Substances; D019715:Tissue Inhibitor of Metalloproteinase-1; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053773:Transforming Growth Factor beta1; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D008715:Methionine; D019255:NADPH Oxidases; D000410:Alanine Transaminase; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse