Expression of the α-tocopherol transfer protein gene is regulated by oxidative stress and common single-nucleotide polymorphisms
Highlights
► Vitamin E is the major lipid-soluble antioxidant. ► α-Tocopherol transfer protein is the only known regulator of vitamin E status. ► Oxidative stress and promoter SNPs regulate expression of the TTPA gene. ► Our findings may explain perplexing results regarding responses to vitamin E supplementation observed in clinical trials.
Section snippets
Cell lines
Because expression of αTTP in primary hepatocytes dramatically decreases after isolation, we employed immortalized human hepatocytes (IHH) that endogenously express the protein [31] as a model system. IHH (generous gift from R. Ray, St. Louis University, St. Louis, MO, USA) were cultured in Dulbecco's modified Eagle's medium supplemented with 5% calf serum (Hyclone Laboratories, Logan, UT, USA) as described in [40].
cAMP response element-binding (CREB) transcription factor knockdown
Lentiviral short hairpin RNA (shRNA) constructs targeted against human CREB
Transcriptional regulation of the tocopherol transfer protein
Examination of murine Ttpa gene expression in 8-day-old C57BL/6 J mice revealed, in agreement with previous reports [21], [46], that αTTP mRNA and protein levels are highest in the liver; significant in the cerebellum, cortex, and kidney; and absent from the intestine and heart (Fig. 1). In all tissues, we observed close correspondence between the levels of the mRNA detected by RT-PCR and those of the protein, revealed by immunoblotting. These data indicate that the Ttpa gene is differentially
Discussion
αTTP is the only known direct regulator of whole-body vitamin E status, yet the mechanisms that regulate its expression are by and large unknown. Our results reveal that expression of the TTPA gene is induced by WY14643 and 9-cis-retinoic acid, ligands that activate the nuclear receptors PPARα and RXR, respectively. Together with the identification of a putative PPAR response element in the TTPA promoter, these data suggest that TTPA transcription is regulated by PPARα–RXR heterodimers [72].
Acknowledgments
This work was supported by NIH Award DK067494 to D.M. and by a pilot award from the Case Comprehensive Cancer Center Support Grant 5P30-CA043703 from the NIH.
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