Deficiency in myeloid differentiation factor-2 and Toll-like receptor 4 expression attenuates non-alcoholic steatohepatitis and fibrosis in mice
Department of Medicine, Division of Gastroenterology
Toll-Like Receptor 4; Adaptor Proteins, Signal Transducing; Fatty Liver
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.
DOI of Published Version
American journal of physiology. Gastrointestinal and liver physiology. 2011 Jan 13. Link to article on publisher's site
American journal of physiology. Gastrointestinal and liver physiology
Csak T, Velayudham A, Hritz I, Petrasek J, Levin I, Lippai D, Catalano D, Mandrekar P, Dolganiuc A, Kurt-Jones EA, Szabo G. (2011). Deficiency in myeloid differentiation factor-2 and Toll-like receptor 4 expression attenuates non-alcoholic steatohepatitis and fibrosis in mice. Gastroenterology Publications. https://doi.org/10.1152/ajpgi.00163.2009. Retrieved from https://escholarship.umassmed.edu/gastroenterology_pp/95