Nutritional depletion in n-3 PUFA in apoE knock-out mice: A new model of endothelial dysfunction associated with fatty liver disease

Scope: Western diets are characterized by low intake of n-3 PUFA compensated by constant amounts of n-6 PUFA. Reduced intake of n-3 PUFA is associated with increased cardiovascular risk, as observed in nonalcoholic fatty liver disease patients. The study aimed to evaluating the impact of dietary n-3 PUFA depletion on endothelial function, an early key event of cardiovascular diseases. Methods and results: C57Bl/6J or apolipoprotein E knock-out (apoE(-/-)) were fed control (CT) or n-3 PUFA-depleted diets (DEF) for 12 wks. Mice fed n-3 DEF diet developed a hepatic steatosis, linked to changes in hepatic expression of genes controlled by Sterol Regulatory Element Binding Protein-1 and -2. Vascular function was assessed on second-and third-order mesenteric arteries and n-3 PUFA-depleted apoE(-/-) mice presented endothelial dysfunction characterized by decreased vasorelaxation in response of acetylcholine. The presence of a nitric oxide synthase (NOS) inhibitor blunted the relaxation in each groups and heme-nitrosylated hemoglobin blood (Hb-NO) level was significantly lower in n-3 PUFA-depleted apoE(-/-) mice. Conclusion: Twelve weeks of n-3 DEF diet promote steatosis and accelerate the process of endothelial dysfunction in apoE(-/-) mice by a mechanism involving the NOS/NO pathway. We propose n-3 PUFA-depleted apoE(-/-) mice as a new model to study endothelial dysfunction related to hepatic steatosis independently of obesity.