Reduced dietray omega-6: omega-3 ratio and 12/15-lipoxygenase deficiency protect from high fat diet-induced steatohepatitis.

LAZIC M, INZAUGARAT ME, POVERO D, CHERÑAVSKY AC, FELDSTEIN A, SEARS DD.

Congreso; 48th Annual Meeting of the European Association for the Study of the Liver (EASL).; 2013

Background: Obesity is associated with metabolic perturbations including liver and adipose tissue inflammation leading to insulin resistance and type 2 diabetes. Diets enriched in omega-6 fatty acids (ω-6) are pro-inflammatory whereas diets enriched with omega-3 fatty acids (ω-3) are anti-inflammatory as they can be metabolized, respectively, to pro- and anti-inflammatory eicosanoids. 12/15-lipoxygenase is an enzyme that produces these metabolites and is induced by high fat diet (HF) feeding. 12/15-lipoxygenase deficient mice are protected from insulin resistance, adipose tissue inflammation, and hepatic lipid accumulation induced by an ω-6-enriched HF. Aim: To investigate the effects of altering dietary ω-6: ω-3 ratio in wild-type (WT) and 12/15 LO knockout (KO) mice on HF-induced tissue inflammation. Methods: Soybean oil rich HF with 45% kcal from fat was used as model of high dietary ω-6: ω-3 ratio of 11:1 (HFHI). Soybean oil was replaced with fish oil to create iso-caloric diet with decreased ω-6: ω-3 ratio to 2.7:1 (HFLO). After 15 weeks on the respective diets, we assessed insulin action, adipose and liver pathophysiology and inflammatory gene expression in WT and KO mice. Results: WT mice fed HFLO exhibited reduced liver but not adipose tissue inflammation compared to WT mice fed HFHI, as evidenced by decreased hepatic expression of IFN-γ (P< 0.01), TNF-α (P< 0.05), IL-12p40 and 18 (P< 0.05), and C-C chemokine receptor type 7 (P< 0.05). Fatty liver, adipose tissue inflammation, and adiposity were not different between HFLO and HFHI-fed groups. However, KO mice were protected from fatty liver and from liver inflammation (decreased IFN-γ, P< 0.05) and lymphocyte homing (decreased C-C motif chemokine 19, P< 0.05) induced by HFHI in WT mice. Only the KO mice were protected from HFHI-induced insulin resistance as determined by hyperinsulinemic euglycemic clamp. Conclusions: Nonalcoholic steatohepatitis is characterized by increased ω-6: ω-3 hepatic ratio. High dietary ratio of ω-6: ω-3 commonly found in Western diet may exacerbate this proinflammatory microenvironment. Our study concludes that diet rich in fish oil significantly reduces HF-induced hepatic inflammation. In addition, we conclude that inhibiting the activity of 12/15-lipoxygenase may protect from diet-induced steatohepatitis, as well as enhance insulin action.