{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:50:56Z","timestamp":1792705856580,"version":"4.5.0"},"reference-count":43,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2011,3]]},"abstract":"<jats:p> 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-\u03b1 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 \u03b1-smooth muscle actin (SMA) staining, procollagen-I, transforming growth factor-\u03b21, \u03b1-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. <\/jats:p>","DOI":"10.1152\/ajpgi.00163.2009","type":"journal-article","created":{"date-parts":[[2011,1,14]],"date-time":"2011-01-14T05:54:16Z","timestamp":1294984456000},"page":"G433-G441","source":"Crossref","is-referenced-by-count":207,"title":["Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice"],"prefix":"10.1152","volume":"300","author":[{"given":"Timea","family":"Csak","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Massachusetts, Medical School, Worcester, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arumugam","family":"Velayudham","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of 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