The nuclear receptor superfamily of ligand-dependent transcription factors functions to regulate a diverse number of genes involved in reproduction, development, metabolism and immune responses [113
]. The ligands for about half of these nuclear receptors have not been identified, so are called “orphan” nuclear receptors. Specific members of the nuclear receptor superfamily bind fat-soluble vitamins A and D; thus, it is not unreasonable to expect that α-tocopherol might also function to control pathways based on hypothetical nuclear receptor binding. There are two nuclear receptor classes that respond to modulation by vitamin E; these are the Pregnane X Receptor (PXR) and the Peroxisome Proliferator-Activated Receptors (PPARs).
PXR regulates a variety of xenobiotic pathways and responds to a wide range of potentially toxic foreign compounds [114
]. With regard to PXR, tocotrienols were more effective ligands than was α-tocopherol in stimulating downstream responses [115
]. Indeed, PXR has been called promiscuous in its ability to bind a variety of ligands [116
]. This characteristic makes PXR ideal for recognizing foreign compounds, but unlikely that α-tocopherol’s specific vitamin function relates to binding to PXR. This α-tocopherol phenomenon is more likely a mechanism involved in the prevention of accumulation of excess vitamin E.
With regard to PPARs, these are three different, but closely related nuclear receptors: PPARα, PPARβ/δ and PPARγ, that are encoded by separate genes [117
]. PPARα is found largely in the liver, where it regulates energy homeostasis, as well as a variety of other functions including heme synthesis, lipoprotein assembly, and cholesterol catabolism. PPARβ/δ is found largely in the gut and placenta. It too is involved in fatty acid catabolism, as well as control of cell proliferation, differentiation and survival. PPARγ is found mainly in the adipose tissue, but also the liver. PPARγ regulates lipid storage and glucose metabolism. In general, PPARs act as lipid sensors that translate changes in fatty acid concentrations into metabolic activity [117
Troglitazone, a member of the thiazolidinedione family of drugs used in treatment of Type 2 diabetes, was one of the first pharmaceutical agents that acted as a PPARγ agonist. Troglitazone is unique in that the chromanol portion of α-tocopherol forms part of its structure [118
]. Similarly to troglitazone, α-tocopherol itself increases PPARγ expression in hepatocytes in vitro, but effective α-tocopherol concentrations in the medium were 50 times higher than usual plasma α-tocopherol concentrations [118
]. Unfortunately, troglitazone, unlike other thiazolidinediones that do not contain an α-tocopherol-like chomanol structure, caused an idiosyncratic liver dysfunction, the cause of which remains unknown, but was sufficiently serious to cause the drug to be withdrawn from the market [119
]. Nonetheless, the reports of PPAR modulation by α-tocopherol have stimulated interest in its ability to function as a PPAR ligand.
When α-, β-, γ-, or δ-tocopherol were tested individually as to whether they could influence transcriptional activity by modulating the activity of various nuclear receptors, the tocopherols positively modulated only the reporter construct containing a consensus element for PPARγ [121
]. Unfortunately, this was not an α-tocopherol specific effect, in that δ-tocopherol caused the greatest response [121
Once again oxidative stress is an important regulator of PPARs [122
]. Oxidative metabolites of linoleic and arachidonic acids are PPAR-ligands, and perhaps more importantly, long chain polyunsaturated fatty acids are potent regulators of PPARs [123
]. Given that it has been pointed out that all cells in culture are under oxidative stress [126
], it is likely that regulation of PPARs by tocopherols is not a specific α-tocopherol-regulatory function, but rather is likely due to modulation of the concentrations or preventing the oxidation of some yet to be identified fatty acid(s).
Molecular effects of α-tocopherol have been studied by analyzing gene expression. Sulzle et al. [122
] fed rats diets for 63 d with 25 or 250 mg α-tocopherol/kg diet containing fresh fat or oxidized fat, then differences in gene expression were evaluated. Irrespective of the dietary vitamin E concentrations, the dietary oxidized fats caused an activation of a series of target PPAR-α genes, as well as, increasing peroxisome proliferation [122
]. In contrast, pigs were studied in an ischemia reperfusion model to test the role of PPARγ in protecting the myocardium from injury. Thiazolidinediones (rosaglitazone and troglitazone) were compared with an α-tocopherol treatment prior to ischemia-reperfusion injury. Remarkably, both troglitazone and α-tocopherol had benefit, causing the authors to conclude that the benefit was due to the antioxidant activity
, not a PPARγ-dependent process. Importantly, α-tocopherol did not materially alter PPARγ expression. Both troglitazone and α-tocopherol preserved myocardial contractile function and stimulated greater lactate uptake. The authors concluded that the antioxidant
, α-tocopherol, prevented the increase in the pro-inflammatory cytokines IL-1, IL-6, and IFN-γ mRNA and protein compared with the ischemic-reperfused myocardium from untreated pigs and compared to the non-injured area.
Taken together, despite the fact that troglitazone was one of the first pharmaceutical agents to modify PPAR function and it contained a chromanol similar to α-tocopherol as part of this molecular structure, it is unlikely that the vitamin function of α-tocopherol is that of a PPAR regulator.