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.

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.

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 α, 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 α were increased in C3−/− mice after ethanol feeding.

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.