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Novel transcriptional activities of vitamin E: inhibition of cholesterol biosynthesis.

ABSTRACT: Vitamin E is a dietary lipid that is essential for vertebrate health and fertility. The biological activity of vitamin E is thought to reflect its ability to quench oxygen- and carbon-based free radicals and thus to protect the organism from oxidative damage. However, recent reports suggest that vitamin E may also display other biological activities. Here, to examine possible mechanisms that may underlie such nonclassical activities of vitamin E, we investigated the possibility that it functions as a specific modulator of gene expression. We show that treatment of cultured hepatocytes with (RRR)-alpha-tocopherol alters the expression of multiple genes and that these effects are distinct from those elicited by another antioxidant. Genes modulated by vitamin E include those that encode key enzymes in the cholesterol biosynthetic pathway. Correspondingly, vitamin E caused a pronounced inhibition of de novo cholesterol biosynthesis. The transcriptional activities of vitamin E were mediated by attenuating the post-translational processing of the transcription factor SREBP-2 that, in turn, led to a decreased transcriptional activity of sterol-responsive elements in the promoters of target genes. These observations indicate that vitamin E possesses novel transcriptional activities that affect fundamental biological processes. Cross talk between tocopherol levels and cholesterol status may be an important facet of the biological activities of vitamin E.

SUBMITTER: Valastyan S

PROVIDER: S-EPMC2531211 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Novel transcriptional activities of vitamin E: inhibition of cholesterol biosynthesis.

Valastyan Scott S Thakur Varsha V Johnson Amy A Kumar Karan K Manor Danny D

Biochemistry 20071221 2

Vitamin E is a dietary lipid that is essential for vertebrate health and fertility. The biological activity of vitamin E is thought to reflect its ability to quench oxygen- and carbon-based free radicals and thus to protect the organism from oxidative damage. However, recent reports suggest that vitamin E may also display other biological activities. Here, to examine possible mechanisms that may underlie such nonclassical activities of vitamin E, we investigated the possibility that it functions ...[more]

PMID: 18095660

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Project description:BackgroundCholesterol plays vital roles in human physiology; abnormal levels have deleterious pathological consequences. In cancer, elevated or reduced expression of cholesterol biosynthesis is associated with good or poor prognosis, but the underlying mechanisms are largely unknown. The limonoid compounds A1542 and A1543 stimulate ERK/MAPK by direct binding, leading to leukemic cell death and suppression of leukemia in mouse models. In this study, we investigated the downstream consequences of these ERK/MAPK agonists in leukemic cells.MethodsWe employed RNAseq analysis combined with Q-RT-PCR, western blot and bioinformatics to identify and confirm genes whose expression was altered by A1542 and A1543 in leukemic cells. ShRNA lentiviruses were used to silence gene expression. Cell culture and an animal model (BALB/c) of erythroleukemia induced by Friend virus were utilized to validate effects of cholesterol on leukemia progression.ResultsRNAseq analysis of A1542-treated cells revealed the induction of all 18 genes implicated in cholesterol biosynthesis. Expression of these cholesterol genes was blocked by cedrelone, an ERK inhibitor. The cholesterol inhibitor lovastatin diminished ERK/MAPK activation by A1542, thereby reducing leukemic cell death induced by this ERK1/2 agonist. Growth inhibition by cholesterol was observed both at the intracellular level, and when orally administrated into a leukemic mouse model. Both HDL and LDL also suppressed leukemogenesis, implicating these lipids as important prognostic markers for leukemia progression. Mechanistically, knockdown experiments revealed that the activation of SREBP1/2 by A1542-A1543 was responsible for induction of only a sub-set of cholesterol biosynthesis genes. Induction of other regulatory factors by A1542-A1543 including EGR1, AP1 (FOS + JUN) LDLR, IER2 and others may cooperate with SREBP1/2 to induce cholesterol genes. Indeed, pharmacological inhibition of AP1 significantly inhibited cholesterol gene expression induced by A1542. In addition to leukemia, high expression of cholesterol biosynthesis genes was found to correlate with better prognosis in renal cancer.ConclusionsThis study demonstrates that ERK1/2 agonists suppress leukemia and possibly other types of cancer through transcriptional stimulation of cholesterol biosynthesis genes.

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Novel transcriptional activities of vitamin E: inhibition of cholesterol biosynthesis.

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Novel transcriptional activities of vitamin E: inhibition of cholesterol biosynthesis.

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