A hundred years have passed since vitamin E was identified as an essential micronutrient for mammals. Since then, many biological functions of vitamin E have been unraveled in both cell and animal models, including antioxidant and anti-inflammatory properties, as well as regulatory activities on cell signaling and gene expression. However, the bioavailability and physiological functions of vitamin E have been considerably shown to depend on lifestyle, genetic factors, and individual health conditions. Another important facet that has been considered less so far is the endogenous interaction with other nutrients. Accumulating evidence indicates that the interaction between vitamin E and other nutrients, especially those that are enriched by supplementation in humans, may explain at least some of the discrepancies observed in clinical trials. Meanwhile, increasing evidence suggests that the different forms of vitamin E metabolites and derivates also exhibit physiological activities, which are more potent and mediated via different pathways compared to the respective vitamin E precursors. In this review, possible molecular mechanisms between vitamin E and other nutritional factors are discussed and their potential impact on physiological and pathophysiological processes is evaluated using published co-supplementation studies.

α-Tocopherol-13′-carboxychromanol (α-T-13′-COOH) is an endogenously formed bioactive α-tocopherol metabolite that limits inflammation and has been proposed to exert lipid metabolism-regulatory, pro-apoptotic, and anti-tumoral properties at micromolar concentrations. The mechanisms underlying these cell stress-associated responses are, however, poorly understood. Here, we show that the induction of G0/G1 cell cycle arrest and apoptosis in macrophages triggered by α-T-13′-COOH is associated with the suppressed proteolytic activation of the lipid anabolic transcription factor sterol regulatory element-binding protein (SREBP)1 and with decreased cellular levels of stearoyl-CoA desaturase (SCD)1. In turn, the fatty acid composition of neutral lipids and phospholipids shifts from monounsaturated to saturated fatty acids, and the concentration of the stress-preventive, pro-survival lipokine 1,2-dioleoyl-sn-glycero-3-phospho-(1′-myo-inositol) [PI(18:1/18:1)] decreases. The selective inhibition of SCD1 mimics the pro-apoptotic and anti-proliferative activity of α-T-13′-COOH, and the provision of the SCD1 product oleic acid (C18:1) prevents α-T-13′-COOH-induced apoptosis. We conclude that micromolar concentrations of α-T-13′-COOH trigger cell death and likely also cell cycle arrest by suppressing the SREBP1-SCD1 axis and depleting cells of monounsaturated fatty acids and PI(18:1/18:1).

Caspase‐1 is a central component of the cellular inflammatory response, in particular with respect to its key role in the activation of the NLRP3 inflammasome pathway. Activation of caspase‐1 ensures the cleavage and release of the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18, as well as the initiation of pyroptosis, that is a distinct form of programmed cell death. Hence, a wide‐ranging analysis of caspase‐1 in cellular systems is of special interest. To meet this requirement, we improved a commercial luminescence‐based caspase‐1 activity assay and combined it with the determination of the expression and release of caspase‐1 protein, using murine J774A.1 macrophages as a model system for in vitro studies. The presented assay procedure offers additional options over commercially available caspase‐1 activity assays as it allows for: (i) The simultaneous analysis of caspase‐1 activity and protein expression (both intracellular as well as secreted protein in supernatant) out of the same cell sample. (ii) A more economical use of valuable compounds and materials and improves the informative value of each measurement, since all results are generated from the same cell sample. Our optimized assay is therefore suitable for an efficient and reliable screening of modulatory effects of compounds of interest at various regulatory stages of the caspase‐1 system.

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