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dc.contributor.authorCsak, Timea
dc.contributor.authorVelayudham, Arumugam
dc.contributor.authorHritz, Istvan
dc.contributor.authorPetrasek, Jan
dc.contributor.authorLevin, Ivan
dc.contributor.authorLippai, Dora
dc.contributor.authorCatalano, Donna
dc.contributor.authorMandrekar, Pranoti
dc.contributor.authorDolganiuc, Angela
dc.contributor.authorKurt-Jones, Evelyn A.
dc.contributor.authorSzabo, Gyongyi
dc.date2022-08-11T08:08:37.000
dc.date.accessioned2022-08-23T16:01:38Z
dc.date.available2022-08-23T16:01:38Z
dc.date.issued2011-01-15
dc.date.submitted2011-03-09
dc.identifier.citationAmerican journal of physiology. Gastrointestinal and liver physiology. 2011 Jan 13. <a href="http://dx.doi.org/10.1152/ajpgi.00163.2009">Link to article on publisher's site</a>
dc.identifier.issn0193-1857 (Linking)
dc.identifier.doi10.1152/ajpgi.00163.2009
dc.identifier.pmid21233280
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31172
dc.description.abstractToll-like receptor 4 (TLR4), and its co-receptor, Myeloid Differentiation Factor 2 (MD-2), are key in recognition of lipopolysaccharide (LPS) and activation of pro-inflammatory pathways. Here we tested the hypothesis that TLR4 and its co-receptor MD-2 play a central role in non-alcoholic steatohepatitis (NASH) and liver fibrosis in non-alcoholic fatty liver disease. Mice of control genotypes and those deficient in MD-2 or TLR4 (knock-out, KO) received methionine-choline-deficient (MCD) or methionine-choline-supplemented (MCS) diet. In mice of control genotypes MCD diet resulted in non-alcoholic steatohepatitis, liver triglycerides accumulation and increased Thiobarbituric Acid Reactive Substances (TBARS), a marker of lipid peroxidation, compared to MCS diet. These features of NASH were significantly attenuated in MD-2-KO and TLR4-KO mice. Serum alanine aminotransferase (ALT), 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 TNFalpha and nictoinamide adenine dinucleotide phosphate (NADPH) oxidase complex mRNA expression and activation, was significantly lower in MCD-diet-fed MD-2-KO and TLR4-KO compared to corresponding genotype control mice. Markers of liver fibrosis (collagen by Sirius red and alphaSMA staining, procollagen-I, TGFbeta1,alphaSMA, MMP2 and TIMP1 mRNA) were attenuated in MD2- and TLR4-KO compared to 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=21233280&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1152/ajpgi.00163.2009
dc.subjectToll-Like Receptor 4
dc.subjectAdaptor Proteins, Signal Transducing
dc.subjectFatty Liver
dc.subjectGastroenterology
dc.titleDeficiency in myeloid differentiation factor-2 and Toll-like receptor 4 expression attenuates non-alcoholic steatohepatitis and fibrosis in mice
dc.typeJournal Article
dc.source.journaltitleAmerican journal of physiology. Gastrointestinal and liver physiology
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gastroenterology_pp/95
dc.identifier.contextkey1862013
html.description.abstract<p>Toll-like receptor 4 (TLR4), and its co-receptor, Myeloid Differentiation Factor 2 (MD-2), are key in recognition of lipopolysaccharide (LPS) and activation of pro-inflammatory pathways. Here we tested the hypothesis that TLR4 and its co-receptor MD-2 play a central role in non-alcoholic steatohepatitis (NASH) and liver fibrosis in non-alcoholic fatty liver disease. Mice of control genotypes and those deficient in MD-2 or TLR4 (knock-out, KO) received methionine-choline-deficient (MCD) or methionine-choline-supplemented (MCS) diet. In mice of control genotypes MCD diet resulted in non-alcoholic steatohepatitis, liver triglycerides accumulation and increased Thiobarbituric Acid Reactive Substances (TBARS), a marker of lipid peroxidation, compared to MCS diet. These features of NASH were significantly attenuated in MD-2-KO and TLR4-KO mice. Serum alanine aminotransferase (ALT), 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 TNFalpha and nictoinamide adenine dinucleotide phosphate (NADPH) oxidase complex mRNA expression and activation, was significantly lower in MCD-diet-fed MD-2-KO and TLR4-KO compared to corresponding genotype control mice. Markers of liver fibrosis (collagen by Sirius red and alphaSMA staining, procollagen-I, TGFbeta1,alphaSMA, MMP2 and TIMP1 mRNA) were attenuated in MD2- and TLR4-KO compared to 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.</p>
dc.identifier.submissionpathgastroenterology_pp/95
dc.contributor.departmentDepartment of Medicine, Division of Gastroenterology


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