Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis. Possible reasons for the NAFLD epidemic in industrialized countries are the high intake of pro-inflammatory n-6 polyunsaturated fatty acids (n-6 PUFAs) and low consumption of healthy n-3 PUFAs. Due to their anti-inflammatory properties, n-3 PUFAs may have the potential to alleviate chronic liver disease. Herein, we examined the therapeutic effect of increased n-3 PUFA tissue levels in fat-1 transgenic mice on progressive NASH.
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. Unlike all other mammals, fat-1 transgenic mice ubiquitously express an n-3 fatty acid desaturase, which converts n-6 to 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 were significantly 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 (Cd36 and Plin3, respectively) was significantly down-regulated in 6 week old but not 8 week old fat-1 transgenic STZ/HFD treated mice.
Conclusions: Endogenously elevated n-3 PUFA levels in fat-1 transgenic mice transiently delay the onset of STZ/HFD induced NASH but failed to efficiently protect from NASH development.
Keywords: Non-alcoholic fatty liver disease (NAFLD); fat-1; n-6/n-3; non-alcoholic steatohepatitis (NASH); steatosis.
2019 Hepatobiliary Surgery and Nutrition. All rights reserved.
Conflict of interest statement
Conflicts of Interest: The authors have no conflicts of interest to declare.
n-3 PUFAs reduce tumor load and improve survival in a NASH-tumor mouse model.Ther Adv Chronic Dis. 2019 Sep 5;10:2040622319872118. doi: 10.1177/2040622319872118. eCollection 2019. Ther Adv Chronic Dis. 2019. PMID: 31523414 Free PMC article.
Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice.J Hepatol. 2018 Apr;68(4):773-782. doi: 10.1016/j.jhep.2017.11.040. Epub 2017 Dec 20. J Hepatol. 2018. PMID: 29273476
Impact of dietary fat on the development of non-alcoholic fatty liver disease in Ldlr-/- mice.Proc Nutr Soc. 2016 Feb;75(1):1-9. doi: 10.1017/S002966511500244X. Epub 2015 Aug 18. Proc Nutr Soc. 2016. PMID: 26282529 Free PMC article.
Regulation of Cholesterol Metabolism in Liver: Link to NAFLD and Impact of n-3 PUFAs.J Lifestyle Med. 2013 Mar;3(1):19-25. Epub 2013 Mar 31. J Lifestyle Med. 2013. PMID: 26064833 Free PMC article. Review.
[A Future Perspective on the Involvement of n-3 Polyunsaturated Fatty Acid in the Development of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis].Yakugaku Zasshi. 2016;136(4):583-9. doi: 10.1248/yakushi.15-00264-4. Yakugaku Zasshi. 2016. PMID: 27040343 Review. Japanese.