TitleDocosahexaenoic acid attenuates hepatic inflammation, oxidative stress, and fibrosis without decreasing hepatosteatosis in a Ldlr(-/-) mouse model of western diet-induced nonalcoholic steatohepatitis.
Publication TypeJournal Article
Year of Publication2013
AuthorsDepner, CM, Philbrick, KA, Jump, DB
JournalJ Nutr
Volume143
Issue3
Pagination315-23
Date Published2013 Mar
ISSN1541-6100
KeywordsAnimals, Arachidonic Acid, Biomarkers, Diet, Dietary Fats, Disease Models, Animal, Docosahexaenoic Acids, Eicosapentaenoic Acid, Fatty Acid Desaturases, Fatty Liver, Fibrosis, Inflammation, Inflammation Mediators, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Oxidative Stress, Receptors, LDL, RNA, Messenger
Abstract
 

The incidence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with the incidence of obesity. While both NAFLD and NASH are characterized by hepatosteatosis, NASH is characterized by hepatic damage, inflammation, oxidative stress, and fibrosis. We previously reported that feeding Ldlr(-/-) mice a high-fat, high-cholesterol diet containing menhaden oil attenuated several markers of NASH, including hepatosteatosis, inflammation, and fibrosis. Herein, we test the hypothesis that DHA [22:6 (n-3)] is more effective than EPA [20:5 (n-3)] at preventing Western diet (WD)-induced NASH in Ldlr(-/-) mice. Mice were fed the WD supplemented with either olive oil (OO), EPA, DHA, or EPA + DHA for 16 wk. WD + OO feeding induced a severe NASH phenotype, characterized by robust hepatosteatosis, inflammation, oxidative stress, and fibrosis. Whereas none of the C20-22 (n-3) fatty acid treatments prevented WD-induced hepatosteatosis, all 3 (n-3) PUFA-containing diets significantly attenuated WD-induced inflammation, fibrosis, and hepatic damage. The capacity of dietary DHA to suppress hepatic markers of inflammation (Clec4F, F4/80, Trl4, Trl9, CD14, Myd88), fibrosis (Procol1α1, Tgfβ1), and oxidative stress (NADPH oxidase subunits Nox2, p22phox, p40phox, p47phox, p67phox) was significantly greater than dietary EPA. The effects of DHA on these markers paralleled DHA-mediated suppression of hepatic Fads1 mRNA abundance and hepatic arachidonic acid content. Because DHA suppression of NASH markers does not require a reduction in hepatosteatosis, dietary DHA may be useful in combating NASH in obese humans.

DOI10.3945/jn.112.171322
Alternate JournalJ. Nutr.
PubMed ID23303872
PubMed Central IDPMC3713021
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