A LOW DIETARY ù6/ù3 RATIO OR A 12/15-LIPOXYGENASE DEFICIENCY IMPAIR THE DEVELOPMENT OF HEPATIC INFLAMMATION AND STEATOSIS IN MICE

INZAUGARAT ME; LAZIC M; POVERO D; SEARS D.; A.C. CHERÑAVSKY; FELDSTEIN A

Los Cocos, Cordoba

Congreso; LVIII Reunión Anual de la Sociedad Argentina de Inmunología; 2013

Introduction: Western diets, characterized by both dietary omega-6 (ù-6) fatty acid enrichment and ù-3 deficiency contribute to metabolic syndrome, liver steatosis and nonalcoholic fatty liver disease (NAFLD). 12/15-lipoxigenase (LO) is an enzyme that metabolizes ù-6 fatty acids into proinflammatory eicosanoids and ù-3 fatty acids into anti-inflammatory eicosanoids. High fat diet (HFD) feeding induces 12/15-lipoxygenase activity. Objectives: To evaluate the effects of altering dietary ù-6: ù-3 ratio in wild-type (WT) and 12/15 LO knockout mice (KO) on HFD-induced liver inflammation. Methods:C57BL/6 WT or 12/15 LO KO mice were fed with normal chow (NC), with high fat diet (HFD) with a ratio ù6/ù3 of 11:1 (HFDH) or HFD with a ratio ù6/ù3 of 2.7:1 (HFDL). After 15 weeks on the respective diets, we assessed liver histology and inflammatory gene expression in WT and KO mice. IFN-g, TNF-a, MIP-2, KC, IL-10, IL12p40, IL12p35, IL-18, CCL19, CCL21 y CCR7 mRNA expression was analyzed by Real-Time PCR. Fold-change values were calculated using the 2-ÄÄCt method. One-way ANOVA with Bonferroni Post-hoc test correction was used. Results: HFDL fed WT mice and KO mice were protected from hepatic steatosis induced by HFDH. Feeding mice with HFDL was able to reduce the mRNA expression of IFN-g (p<0.05), TNF-a (p<0.05), KC (p<0.05), IL12p40 (p<0.05), IL12p35 (p<0.05), IL-18 (p<0.05), CCL19 (p<0.05) and to increase mRNA expression of CCR7 (p<0.05) observed in HFDH fed mice. 12/15 LO deficiency was capable of decrease expression of IFN-g (p<0.05), MIP-2 (p<0.05), CCL19 (p<0.01) and to augment expression of CCR7 (p<0.05) related to HFDH fed WT mice.Conclusions: Both lowering dietary ù6/ù3 ratio and the absence of 12/15-LO significantly reduced HF-induced hepatic inflammation and steatosis. The translational value of therapeutic approaches based on dietary composition or down modulation of hepatic tissue 12/15-LO expression deserves further investigation.