Tocotrienols Activate Nrf2 Nuclear Translocation and Increase the Antioxidant- Related Hepatoprotective Mechanism in Mice Liver

Abstract

Background: The most common preparation of tocotrienols is the tocotrienol-rich fraction (TRF). This study aimed to investigate whether TRF induced liver Nrf2 nuclear translocation and influenced the expression of Nrf2-regulated genes. Methods: In the Nrf2 induction study, mice were divided into control, 2000 mg/kg TRF and diethyl maleate treated groups. After acute treatment, mice were sacrificed at specific time points. Liver nuclear extracts were prepared and Nrf2 nuclear translocation was detected through Western blotting. To determine the effect of increasing doses of TRF on the extent of liver nuclear Nrf2 translocation and its implication on the expression levels of several Nrf2-regulated genes, mice were divided into 5 groups (control, 200, 500 and 1000 mg/kg TRF, and butylated hydroxyanisole-treated groups). After 14 days, mice were sacrificed and liver RNA extracted for qPCR assay. Results: 2000 mg/kg TRF administration initiated Nrf2 nuclear translocation within 30 min, reached maximum level around 1 h and dropped to half-maximal levels by 24 h. Incremental doses of TRF resulted in dose-dependent increases in liver Nrf2 nuclear levels, along with concomitant dose-dependent increases in the expressions of Nrf2-regulated genes. Conclusion: TRF activated the liver Nrf2 pathway resulting in increased expression of Nrf2-regulated cytoprotective genes.

Effect of Administration of an Equal Dose of Selected Dietary Chemicals on Nrf2 Nuclear Translocation in the Mouse Liver

“…GCLC, GPX1, and CAT have been known to be regulated by Nrf2 [ 13 , 57 ]. In this study, the effects of administration of equal doses of several dietary chemicals on GCLC, GPX1, and CAT gene expression were determined.…”

“…Nuclear extracts from mouse liver tissues were prepared according to a procedure previously described by Atia et al with slight adjustments [ 13 ]. Briefly, 100 mg of liver tissue was homogenized in 1 ml of cold buffer A [50 mM NaCl, 10 mM Hepes pH 8, 1 mM EDTA, 0.5 mM sucrose, 0.5 mM spermidine, 0.15 mM spermine, and 0.2% Triton X-100 ( v / v )] at 4°C.…”

“…The redox-sensitive transcription factor Nrf2 mediates cellular defence against chemical and oxidative stress. Oxidative, chemical, and electrophilic stresses lead to Nrf2 activation and nuclear translocation, which in turn upregulates the expression of several antioxidant defence genes and various phase II detoxifying enzymes, which detoxifies any potential carcinogen thus preventing the formation of cancer [ 11 , 13 , 14 ]. Therefore, in healthy mice (and most possibly in healthy individuals), activation of the Nrf2 pathway by administration of dietary supplements would upregulate the expression of antioxidant proteins and phase II detoxifying enzymes, thus potentially hindering any opportunity for cancer initiation.…”

Tocotrienol in the Management of Nonalcoholic Fatty Liver Disease: A Systematic Review

“…Delta-T3 was shown to inhibit TNFα-induced IL-6 production in RAW264.7 macrophages by inhibiting the phosphorylation of transforming growth factor β-activated kinase 1 upstream of NFκB and increasing the expression of A20 and cylindromatosis, which are inhibitors of NFκB [ 64 ]. Palm T3 was reported to increase nuclear translocation of nuclear factor erythroid 2–related factor 2, which is a transcription factor regulating the expression of various antioxidant enzymes [ 65 ]. These findings point towards the use of T3 to suppress inflammatory and oxidative stress conditions, including NAFLD.…”

Tocotrienol in Pre-Eclampsia Prevention: A Mechanistic Analysis in Relation to the Pathophysiological Framework

“…Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular antioxidants, as it governs the expression of various antioxidants in response to oxidative stress [ 56 ]. Palm TRF up-regulates NRF2 expression, which increases the nuclear translocation of NRF2 in mouse liver [ 57 ]. Moreover, δ-tocotrienol can stabilise the NRF2 activation induced by 5-fluorouracil in human oral keratinocytes, which can cause a sustained increase in the expression of heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1 [ 58 ].…”