Docosahexaenoic acid attenuates Western diet-induced hepatic fibrosis in Ldlr(-/-) mice by targeting the TGFβ-Smad3 pathway

This is the publisher’s final pdf. The published article is copyrighted by the American Society for Biochemistry and Molecular Biology and can be found at: http://www.jlr.org/content/56/10/1936This research was originally published in the Journal of Lipid Research. Lytle, K. A., Depner, C. M., Wong, C. P., & Jump, D. B. Docosahexaenoic acid attenuates Western diet-induced hepatic fibrosis in Ldlr−/− mice by targeting the TGFβ-Smad3 pathway. Journal of Lipid Research. 2015. 56:1936-1946. © the American Society for Biochemistry and Molecular BiologyAccess to this item has been restricted by repository administrators at the request of the publisher until August 27, 2016.DHA (22:6,ω3), but not EPA (20:5,ω3), attenuates Western diet (WD)-induced hepatic fibrosis in a Ldlr[superscript −/−] mouse model of nonalcoholic steatohepatitis. We examined the molecular basis for the differential effect of dietary EPA and DHA on WD-induced hepatic fibrosis. DHA was more effective than EPA at preventing WD-induced effects on hepatic transcripts linked to fibrosis, including collagen 1A1 (Col1A1), transforming growth factor-β (TGFβ) signaling and proteins involved in remodeling the extracellular matrix, including metalloproteases, tissue inhibitors of metalloproteases, and lysyl oxidase subtypes. Examination of the TGFβ pathway showed that mice fed the WD supplemented with either olive oil or EPA had a significant (≥2.5-fold) increase in hepatic nuclear abundance of phospho-mothers against decapentaplegic homolog (Smad)3 when compared with mice fed the reference diet (RD); Smad3 is a key regulator of Col1A1 expression in stellate cells. In contrast, mice fed the WD supplemented with DHA had no increase in phospho-Smad3 when compared with mice fed the RD. Changes in hepatic phospho-Smad3 nuclear content correlated with proCol1A1 mRNA and protein abundance. Pretreatment of human LX2 stellate cells with DHA, but not other unsaturated fatty acids, blocked TGFβ1-mediated induction of Col1A1. In conclusion, DHA attenuates WD-induced fibrosis by targeting the TGFβ-Smad3-Col1A1 pathway in stellate cells