α-Tocopherol-13'-Carboxychromanol Induces Cell Cycle Arrest and Cell Death by Inhibiting the SREBP1-SCD1 Axis and Causing Imbalance in Lipid Desaturation.

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).

Vitamin E and Metabolic Health: Relevance of Interactions with Other Micronutrients.

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.

The vitamin E long-chain metabolite α-13'-COOH affects macrophage foam cell formation via modulation of the lipoprotein lipase system.

The α-tocopherol-derived long-chain metabolite (α-LCM) α-13'-carboxychromanol (α-13'-COOH) is formed via enzymatic degradation of α-tocopherol (α-TOH) in the liver. In the last decade, α-13'-COOH has emerged as a new regulatory metabolite revealing more potent or even different effects compared with its vitamin precursor α-TOH. The detection of α-13'-COOH in human serum has further strengthened the concept of its physiological relevance as a potential regulatory molecule. Here, we present a new facet on the interaction of α-13'-COOH with macrophage foam cell formation. We found that α-13'-COOH (5 µM) increases angiopoietin-like 4 (ANGPTL4) mRNA expression in human THP-1 macrophages in a time- and dose-dependent manner, while α-TOH (100 µM) showed no effects. Interestingly, the mRNA level of lipoprotein lipase (LPL) was not influenced by α-13'-COOH, but α-TOH treatment led to a reduction of LPL mRNA expression. Both compounds also revealed different effects on protein level: while α-13'-COOH reduced the secreted amount of LPL protein via induction of ANGPTL4 cleavage, i.e. activation, the secreted amount of LPL in the α-TOH-treated samples was diminished due to the inhibition of mRNA expression. In line with this, both compounds reduced the catalytic activity of LPL. However, α-13'-COOH but not α-TOH attenuated VLDL-induced lipid accumulation by 35%. In conclusion, only α-13'-COOH revealed possible antiatherogenic effects due to the reduction of VLDL-induced foam cell formation in THP-1 macrophages. Our results provide further evidence for the role of α-13'-COOH as a functional metabolite of its vitamin E precursor.

Inflammatory Diseases and Vitamin E-What Do We Know and Where Do We Go?

Inflammation-driven diseases and related comorbidities, such as the metabolic syndrome, obesity, fatty liver disease, and cardiovascular diseases cause significant global burden. There is a growing body of evidence that nutrients alter inflammatory responses and can therefore make a decisive contribution to the treatment of these diseases. Recently, the inflammasome, a cytosolic multiprotein complex, has been identified as a key player in inflammation and the development of various inflammation-mediated disorders, with nucleotide-binding domain and leucine-rich repeat pyrin domain (NLRP) 3 being the inflammasome of interest. Here an overview about the cellular signaling pathways underlying nuclear factor "kappa-light-chain-enhancer" of activated B-cells (NF-κB)- and NLRP3-mediated inflammatory processes, and the pathogenesis of the inflammatory diseases atherosclerosis and non-alcoholic fatty liver disease (NAFLD) is provided; next, the current state of knowledge for drug-based and dietary-based interventions for treating cardiovascular diseases and NAFLD is discussed. To date, one of the most important antioxidants in the human diet is vitamin E. Various in vitro and in vivo studies suggest that the different forms of vitamin E and also their derivatives have anti-inflammatory activity. Recent publications suggest that vitamin E-and possibly metabolites of vitamin E-are a promising therapeutic approach for treating inflammatory diseases such as NAFLD.