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 non-classical 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-α-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.The term vitamin E refers to a family of structurally related neutral plant lipids that are critical for vertebrate health and fertility. Numerous studies established that members of the vitamin E family are efficient chain-breaking radical scavengers both in vitro and in vivo, and led to the definition of vitamin E as the most important lipid-soluble antioxidant (1). While all isoforms of vitamin E possess comparable radical trapping activity in vitro (2), RRR-α-tocopherol (denoted herein as αTOH) exhibits the highest potency in biological assays (3). This vitamer preference stems from the combined activities of the hepatic α-tocopherol transfer protein (TTP) that selectively retains αTOH (3-5), and the catabolic actions of hepatic enzymes that degrade other forms of vitamin E to water-soluble products (6).The selectivity for αTOH raises the possibility that this vitamer has unique biological roles, in addition to its anti-oxidant function. Indeed, novel regulatory properties have been ascribed in recent years to αTOH, including the modulation of apoptosis, cell adhesion, and specific enzymatic activities (cf. 7, 8). Moreover, αTOH was shown to regulate the expression levels of several mRNAs and proteins, such as collagen α1 (9), the scavenger receptors SR-BI (10) and CD36 (11,12), α-tropomyosin (13), the nuclear receptor PPARγ (14), and the adhesion molecule VCAM-I (15). These anecdotal observations were further supported by several studies that documented genomic responses to vitamin E using expression-profiling § To whom correspondence should be addressed at: Schoo...

Novel metabolites and roles for α-tocopherol in humans and mice discovered by mass spectrometry–based metabolomics

“…Downregulation of the cholesterol homeostatic genes Hmgcr and Hmgcs was also seen, which was previously shown in human hepatocytes supplemented with a-tocopherol (25). The mechanism of downregulation of these genes, and thus cholesterol production seen in human hepatocytes, was due to attenuation of the transcriptional response of the sterol response elements in the promoter of these genes mediated by sterol response element binding protein-2 (25). Vitamin E was previously shown to decrease steatosis and inflammation in patients with nonalcoholic steatohepatitis (26).…”

Tocopherol Transfer Protein Sensitizes Prostate Cancer Cells to Vitamin E

“…Measurements of Intracellular ROS-Cells were cultured in serum-free RPMI 1640 medium for 2 days, washed twice with phenol red-free Hanks' buffered salt solution (Hyclone), and incubated for 2 h with dihydrofluorescein diacetate (10 g/ml, Invitrogen) and 2Ј,7Ј-dichlorofluorescein fluorescence (excitation, 485 nm; emission, 535 nm) measured in a plate reader as described earlier (36). Duplicate plates were stained with the DNA stain Hoechst 33258 (Invitrogen, 5 g/ml), and fluorescence (excitation, 365 nm; emission, 460 nm) was measured on a plate reader.…”

Laser-Induced Oxidation of Cholesterol Observed During MALDI-TOF Mass Spectrometry

“…These studies have mainly been done in solution. We have used the traditional free radical scavengers α-tocopherol [27,28] and tertiarybutyl hydroquinone [26] in an attempt to diminish the intensity of the radical cation peaks in the gas phase. The addition of TBHQ was ineffective at lowering the radical cation peaks of cholesterol dissolved in acetonitrile.…”