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Access Type

WSU Access

Date of Award

January 2017

Degree Type

Thesis

Degree Name

M.S.

Department

Nutrition and Food Science

First Advisor

Pramod Khosla

Abstract

Tocotrienols are naturally occurring bioactive compounds which possess beneficial effects on multiple chronic diseases including atherosclerosis and cancer. It is believed to exert atheroprotective effects via promoting reverse cholesterol transport, a process that removes excess cholesterol from the body. Cholesterol efflux is an early step in reverse cholesterol transport and impaired cholesterol efflux is known to trigger foam cell formation, a hallmark of atherosclerosis. An increase in cholesterol efflux and decrease in cholesterol influx in macrophages has been suggested to reduce atherosclerosis risk by reducing foam cell formation. In addition, tocotrienols have shown anti-cancer effects on Non-small cell lung cancer (NSCLC). Therefore, the objective of this study was to investigate time and dose dependent effects of Tocotrienols Rich Fraction (TRF) derived from Palm oil (74.68% Tocotrienols and 23.5% Tocopherols) on PPAR-γ, a key modulator of cholesterol efflux, its downstream cholesterol influx (SRA1, CD 36) and genes related to efflux (LXR-α, ABCA1, ABCG1, SRB1) in J774A.1 macrophages. To confirm contents of TRF capsules are active, anti-cancer effects of TRF on NSCLC cell lines were used. Effects of three TRF batches (TRF 1, TRF 2 and TRF 3) on A549 cell proliferation were determined using MTS assay (0,40,80,120 µg/ml). Western-blot analysis was used to test the effects of TRF 1 on Notch-1 expression, a protein involved in cancer cell proliferation. All three different batches significantly reduced A549 cell growth, starting from 80 µg/ml and TRF -1 dose dependently decreased Notch-1 protein expression. Non-toxic concentrations range of TRF-2 for J774A.1 cells were determined using MTS assay and the effect of TRF-2 on PPAR-γ, influx and efflux genes were explored using real-time PCR. Based on MTS assay results, concentrations of 0, 8, 16 µg/ml of TRF-2 were selected for 24 and 48 hour treatments for J774A.1 cells. According to PCR data, treatment with 16 µg/ml TRF-2 for 48 hours showed the highest significant increase of PPAR-γ, SRB1, and CD 36 expression, and the highest significant decrease in SRA1 and ABCA1 expression compared to the control under tested conditions. At these conditions, both LXR- α and ABCG1 were not significantly changed. Taken together, our data suggests that TRF impacts both influx and efflux genes via upregulation of PPAR-γ, such that the net effect favors increase in cholesterol efflux.

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