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Differential contributions of C3, C5, and decay-accelerating factor to ethanol-induced fatty liver in mice
Authors:Pritchard Michele T  McMullen Megan R  Stavitsky Abram B  Cohen Jessica I  Lin Feng  Medof M Edward  Nagy Laura E
Institution:Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44905, USA.
Abstract:BACKGROUND AND AIMS: The complement pathway is an important component of the innate and adaptive immune response. Here we tested the hypothesis that activation of complement is required for development of ethanol-induced fatty liver. METHODS: Wild-type mice and mice lacking the third (C3) or fifth (C5) components of the complement activation pathway, as well as mice lacking decay-accelerating factor (CD55/DAF), a complement regulatory protein, were fed Lieber-DeCarli ethanol-containing diets for 6 weeks or pair-fed control diets. RESULTS: Ethanol feeding to wild-type mice increased C3a in plasma. Wild-type and C5-/- mice fed the ethanol diet developed hepatic steatosis characterized by microvesicular and macrovesicular lipid accumulation and increased triglyceride content. C3-/- mice did not develop steatosis, while CD55/DAF-/- mice accumulated even more hepatic triglyceride after ethanol feeding than wild-type mice. Levels of serum alanine aminotransferase and hepatic tumor necrosis factor alpha, indicators of hepatocyte injury and inflammation, respectively, were increased in wild-type and CD55/DAF-/- mice but not in C5-/- mice after ethanol feeding. In contrast to the protective effect of C3-/- against ethanol-induced steatosis, levels of both alanine aminotransferase and tumor necrosis factor alpha were increased in C3-/- mice after ethanol feeding. CONCLUSIONS: Here we have identified several elements of the complement system as important contributors to ethanol-induced fatty liver. C3 contributed primarily to the accumulation of triglyceride in the liver, whereas C5 was involved in inflammation and injury to hepatocytes. Further, the absence of CD55/DAF exacerbated these responses, suggesting that CD55/DAF serves as a barrier to ethanol-induced fatty liver.
Keywords:ASP  acylation-stimulating protein  C3  third component of the complement system  C5  fifth component of the complement system  CYP2E1  cytochrome P450 2E1  DAF  decay-accelerating factor  ELISA  enzyme-linked immunosorbent assay  IFN  interferon  IL  interleukin  LPS  lipopolysaccharide  TNF  tumor necrosis factor
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