Diets with low n-6:n-3 PUFA ratio protects rats from fructose-induced dyslipidemia and associated hepatic changes: Comparison between 18:3 n-3 and long-chain n-3 PUFA.

Key Points

Dietary fructose plays a critical role in the development of metabolic syndrome (MetS), a metabolic disorder defined by the presence of dyslipidemia, insulin resistance, hypertension, and visceral obesity. Hypertriglyceridemia is a critical component of the MetS and contributes to the development and worsening of other MetS components like insulin resistance. Fructose consumption elevates the circulatory triglyceride levels in both human subjects and animal models. Fructose feeding increases the expression of genes involved in lipogenesis by inducing various transcriptions factors like sterol regulatory element-binding transcription factor 1c (SREBP1c), peroxisome proliferator-activated receptor-gamma (PPARγ), liver X receptor alpha (LXRα) and carbohydrate-response element-binding protein (ChREBP) in the liver. Fructose consumption further induces hepatic inflammation, oxidative, and endoplasmic reticulum (ER) stress and elevates the hepatic expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and hexose-6-phosphate dehydrogenase (H6PD), enzymes involved in the generation of active glucocorticoids. This study investigated the effect of diets with a lower n-6:n-3 PUFA ratio on HFrD-induced hypertriglyceridemia and associated hepatic gene expression. The effects of these diets on HFrD-induced hepatic oxidative stress along with the expression of genes related to inflammation, endoplasmic reticulum (ER) stress, and prereceptor metabolism of glucocorticoids was assessed. The effects of 18:3 n-3 PUFA (ALA) and LC n-3 PUFA (DHA and EPA) on these parameters to were determined. Feeding rats with diets with a decreased n-6:n-3 ratio by either supplementing ALA or LC n-3 PUFA protected rats from fructose-induced hypertriglyceridemia and hypercholesterolemia. Both ALA and LC n-3 PUFA ameliorated the fructose-induced oxidative stress and corrected the hepatic lipogenic and inflammatory gene expression. ALA and LC n-3 PUFA supplementation also reversed the fructose-induced expression of 11β-HSD1 gene, which plays a critical role in the generation of the active glucocorticoids in the tissues. Here diets with decreased n-6:n-3 PUFA ratio corrected the HFrD-induced oxidative stress evidenced by normalized superoxide dismutase and glutathione peroxidase activities along with lipid peroxidation and p47 phox gene expression. Further, when compared between ALA and LC n-3 PUFA, LC n-3 PUFA provided better protection from hepatic lipid peroxidation, indicating decreasing dietary n-6:n-3 ratio by supplementing LC n-3 PUFA is more effective in counteracting HFrD-induced hepatic oxidative stress than supplementing ALA. In this study, twenty-four weeks of HFrD-feeding significantly increased hepatic 11β-HSD1 expression without altering the H6PD expression, suggesting the possible increase in the tissue active glucocorticoid levels. In conclusion, feeding diets with decreased dietary n-6:n-3 ratio either by supplementing ALA or LC n-3 PUFA decreases the hepatic 11β-HSD1 expression, providing one of the mechanisms involved in the protective effects of n-3 PUFA on HFrD-induced hypertriglyceridemia and the hepatic inflammation and oxidative stress. Results demonstrated that partial replacement of dietary n-6 PUFA with n-3 PUFA (ALA or LC n-3 PUFA) effectively prevented high fructose-induced dyslipidemia, hepatic oxidative stress, and inflammation. LC n-3 PUFA is more effective in preventing high fructose-induced oxidative stress and inflammation. The present western diet contains high levels of n-6 PUFA and sugar particularly fructose and deficient in n-3 PUFA which might contribute to the recent increase in the prevalence of metabolic syndrome. Hence moderating the intake of n-6 PUFA and increasing the intake of n-3 PUFA may be beneficial for the prevention of metabolic syndrome and associated chronic diseases.