Mechanism Study Of The Preventive Effect Of Tocotrenol On Atherosclerosis

Cardiovascular disease is a major health risk. Atherosclerosis is a key factor to the development of cardiovascular disease. Extensive studies have shown that dyslipidemia and inflammation contribute to the development of atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs) are two nuclear hormone receptors (NHR) that play very important roles in controlling lipid metabolism and anti-atherosclerosis.PPARs are ligand-inducible transcription factors. They can protect from atherosclerosis through anti-inflammatory actions and regulating the expression of their target genes in lipid metabolism. Importantly, PPARs enhance reverse cholesterol transport through modulating the mRNA expression of LXRα(liver X receptor). LXRαregulates cholesterol biogenesis, cholesterol absorption, and reverse cholesterol transport as part of the anti-atherosclerosis mechanism.Vitamin E (V_E), a fat soluble vitamin, is a mixture of tocopherols and tocotrienols. It has been reported that V_E has anti-oxidant, anti-cancer and anti-atherosclerosis activities. Interestingly, tocotrienols have been demonstrated to prevent the development of atherosclerosis in animal models and small scale clinical trials. We hypothesize that tocotrienols prevent atherosclerosis through modulating the activities of PPARs.Using a luciferase reporter assay, we firstly tested the activation of PPARs by tocotrienol rich fraction of palm oil (TRF) and its anti-inflammatory ability in a mice macrophage cell line RAW264.7. The expression levels of PPARs target genes regulated by TRF were determined in human monocyte cell line THP-1 by qRT-PCR. Using ApoE^-/- mice as an atherosclerotic model, we measured the influence of TRF on atherosclerotic plaque, serum lipid levels and related gene expression in ApoE^-/- mice.In our study, we found that TRF activated PPARs but not LXRs. TRF also showed good activity on anti-inflammation. TRF up-regulated PPAR-target gene LXRαand its down-stream target genes cholesterol transporters and apolipoproteins. In animal model, compared to control group, TRF attenuated the development of atherosclerosis in ApoE^-/- mice. It improved glucose metabolism and increased insulin sensitivity of ApoE^-/- mice. TRF also up-regulated LXRαand its down-stream target genes cholesterol transporters and apolipoproteins in liver of ApoE^-/- mice. The gene expression of adiponetin and glucose transporter 4 (Glut 4) was increased by TRF in white adipose tissue of ApoE^-/- mice. Our results showed that TRF attenuated the development of atherosclerosis in ApoE^-/- mice and the effect of this may at least partially through modulating the activities of PPARs.