Dose-dependent Modulation of Lipid Parameters, Cytokines and RNA by δ-tocotrienol in Hypercholesterolemic Subjects Restricted to AHA Step-1 Diet

Abstract

Aims: Evaluate the consumption of δ-tocotrienol (free from tocopherols) on serum lipid parameters, and several cytokines (TNF-α, IL-4, IL-6, IL-8, IL-10), including gene expression and circulating microRNAs (miRNAs) in hypercholesterolemic subjects. Study Design: The present preliminary dose-response study consisted of six phases. All hypercholesterolemic subjects took increasing doses of δ-tocotrienol (125, 250, 500,750 mg/d) plus AHA Step-1 diet for 4 weeks during the 30 weeks study period. Methodology: Hypercholesterolemic (n = 31; serum cholesterol > 5.2 mmol/L) subjects (males-26/females 5; age range 50-71 years) were enrolled in the study from WahCantonment, Pakistan. Serum lipid parameters were measured by auto analyzers. Various plasma cytokines, cDNA, and miRNAs were estimated by Signosis kits. Results: All participants (n = 31) completed all phases of study. The δ-tocotrienol plus AHA Step-1 diet caused reductions in lipid parameters in a dose-dependent manner with maximum effects on serum total cholesterol (15%), LDL-cholesterol (18%), triglycerides (14%) with 250 mg/d dose (P< 0.001). Doses above 500 mg/d resulted ininduction in levels of all lipid parameters, except HDL-cholesterol. The cytokines associated with cardiovascular disease (plasma TNF-α, IL-2, IL-4, IL-6, IL-8, IL-10) were all down-regulated 39%-64% by δ-tocotrienol treatment (P< 0.01). Similar results were obtained with gene expression of these cytokines using whole blood messenger-RNA. In contrast, circulating miRNA-7a, miRNA-15a, miRNA-20a (anti-angiogenic), miRNA-21, miRNA-29a, miRNA-92a, miRNA-200, miRNA-206 (skeletal muscle regeneration) down-regulated in hypercholesterolemic subjects, were up-regulated by δ-tocotrienol treatment as compared to baseline (P< 0.01). Conclusions: The present results confirm that consumption of δ-tocotrienol plus AHA Step-1 diet causes significant reduction in serum lipid parameters and several cytokines (TNF-α, IL-2, IL-4, IL-6, IL-8, IL-10) at a low optimal dose (250 mg/d). The capacity of δ-tocotrienol to modulate inflammation is partly attributable to dose-dependent properties of inhibition/activation, which may play a major role in future treatment of cardiovascular diseases.