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Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver diseaseworldwide, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis. Possiblereasons for the NAFLD epidemic in industrialized countries are the high intake of pro-inflammatory n-6polyunsaturated fatty acids (n-6 PUFAs) and low consumption of healthy n-3 PUFAs. Due to their antiinflammatoryproperties, n-3 PUFAs may have the potential to alleviate chronic liver disease. Herein, weexamined the therapeutic effect of increased n-3 PUFA tissue levels in fat-1 transgenic mice on progressiveNASH.Methods: Disease was induced in mice by streptozotocin and high fat diet (STZ/HFD) resulting in NASH.NAFLD in 6 and 8 weeks old wild type and fat-1 transgenic STZ/HFD treated mice was analyzed. Unlikeall other mammals, fat-1 transgenic mice ubiquitously express an n-3 fatty acid desaturase, which converts n-6to n-3 PUFAs, leading to increased n-3 and decreased n-6 PUFA tissue contents.Results: Liver damage, NAFLD activity score (NAS), hepatic lipid accumulation and inflammation weresignificantly reduced in fat-1 transgenic STZ/HFD treated mice in the early (6 weeks) but not late (8 weeks)phase of NASH. Simultaneously, mRNA expression of genes involved in fatty acid uptake and storage (Cd36and Plin3, respectively) was significantly down-regulated in 6 week old but not 8 week old fat-1 transgenicSTZ/HFD treated mice.Conclusions: Endogenously elevated n-3 PUFA levels in fat-1 transgenic mice transiently delay the onsetof STZ/HFD induced NASH but failed to efficiently protect from NASH development.