TitleDocosahexaenoic acid attenuates Western diet-induced hepatic fibrosis in Ldlr-/- mice by targeting the TGFβ-Smad3 pathway.
Publication TypeJournal Article
Year of Publication2015
AuthorsLytle KA, Depner CM, Wong CP, Jump DB
JournalJ Lipid Res
Date Published2015 Oct
KeywordsAnimals, Collagen Type I, Diet, Western, Dietary Supplements, Disease Models, Animal, Docosahexaenoic Acids, Eicosapentaenoic Acid, Fatty Acids, Unsaturated, Hepatic Stellate Cells, Liver Cirrhosis, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Non-alcoholic Fatty Liver Disease, Smad3 Protein, Transforming Growth Factor beta

DHA (22:6,ω3), but not EPA (20:5,ω3), attenuates Western diet (WD)-induced hepatic fibrosis in a Ldlr(-/-) 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.

Alternate JournalJ. Lipid Res.
PubMed ID26315048
PubMed Central IDPMC4583081
Grant ListR01 DK043220 / DK / NIDDK NIH HHS / United States
R01 DK094600 / DK / NIDDK NIH HHS / United States
DK 094600 / DK / NIDDK NIH HHS / United States
DK 43220 / DK / NIDDK NIH HHS / United States