Novel transcriptional activities of vitamin E: inhibition of cholesterol biosynthesis.
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.
Valastyan
Scott
S
Cornell University, Ithaca, New York 14853, and Case Western Reserve University, Cleveland, Ohio 44106, USA.
Thakur
Varsha
V
Johnson
Amy
A
Kumar
Karan
K
Manor
Danny
D
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis*; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015203:Reproducibility of Results; D027602:Serum Response Element; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014810:Vitamin E / Q000494:pharmacology*; D024502:alpha-Tocopherol / Q000494:pharmacology
D017382:Reactive Oxygen Species; D051782:Sterol Regulatory Element Binding Protein 2; D014810:Vitamin E; D002784:Cholesterol; D024502:alpha-Tocopherol; D000111:Acetylcysteine