Docosahexaenoic acid attenuates hepatic inflammation, oxidative stress, and fibrosis without decreasing hepatosteatosis in a Ldlr(-/-) mouse model of western diet-induced nonalcoholic steatohepatitis

J Nutr. 2013 Mar;143(3):315-23. doi: 10.3945/jn.112.171322. Epub 2013 Jan 9.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Arachidonic Acid / metabolism
  • Biomarkers / metabolism
  • Delta-5 Fatty Acid Desaturase
  • Diet / adverse effects
  • Dietary Fats / pharmacology
  • Dietary Fats / therapeutic use
  • Disease Models, Animal
  • Docosahexaenoic Acids / metabolism
  • Docosahexaenoic Acids / pharmacology
  • Docosahexaenoic Acids / therapeutic use*
  • Eicosapentaenoic Acid / metabolism
  • Eicosapentaenoic Acid / pharmacology*
  • Fatty Acid Desaturases / genetics
  • Fatty Acid Desaturases / metabolism
  • Fatty Liver / drug therapy*
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Fibrosis / etiology
  • Fibrosis / metabolism
  • Fibrosis / prevention & control
  • Inflammation / etiology
  • Inflammation / metabolism
  • Inflammation / prevention & control*
  • Inflammation Mediators / metabolism
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidative Stress / drug effects*
  • RNA, Messenger / metabolism
  • Receptors, LDL / genetics*
  • Receptors, LDL / metabolism

Substances

  • Biomarkers
  • Delta-5 Fatty Acid Desaturase
  • Dietary Fats
  • Inflammation Mediators
  • RNA, Messenger
  • Receptors, LDL
  • Docosahexaenoic Acids
  • Arachidonic Acid
  • Eicosapentaenoic Acid
  • Fatty Acid Desaturases
  • FADS1 protein, human