Impaired ability of patients with familial isolated vitamin E deficiency to incorporate α-tocopherol into lipoproteins secreted by the liver

Department of Medicine, New York University School of Medicine, New York 10016.
Journal of Clinical Investigation (Impact Factor: 13.22). 03/1990; 85(2):397-407. DOI: 10.1172/JCI114452
Source: PubMed


Plasma and lipoprotein alpha-tocopherol concentrations of four patients with familial isolated vitamin E deficiency and six control subjects were observed for 4 d after an oral dose (approximately 15 mg) of RRR-alpha-tocopheryl acetate labeled with six deuterium atoms (d6-tocopherol). Chylomicron d6-tocopherol concentrations were similar in the two groups. d6-Tocopherol concentrations of plasma, very low (VLDL), low (LDL), and high (HDL) density lipoproteins were similar in the two groups only during the first 12 h; then these were significantly lower, and the rate of disappearance faster, in the patients. The times (tmax) of the maximum chylomicron d6-tocopherol concentrations were similar for the two groups, but tmax values in the controls increased in the order: chylomicrons less than VLDL less than or equal to LDL approximately HDL, while the corresponding values in the patients were similar to the chylomicron tmax. Thus, plasma d6-tocopherol in controls increased during chylomicron and VLDL catabolism, whereas in patients it increased only during chylomicron catabolism, thereby resulting in a premature and faster decline in the plasma tocopherol concentration due to a lack of d6-tocopherol secretion from the liver. We suggest that these patients are lacking or have a defective liver "tocopherol binding protein" that incorporates alpha-tocopherol into nascent VLDL.

Download full-text


Available from: Ronald J Sokol, Sep 30, 2015
8 Reads
  • Source
    • "Familial isolated deficiency of vitamin E (VED; MIM 277460) is a recessive disorder caused by mutations in the gene encoding α-tocopherol transfer protein, TTPA (Ouahchi et al. 1995). Deficiency of this protein prohibits α-tocopherols, members of the vitamin E family of molecules, from being incorporated into plasma VLDL (Traber et al. 1990) and results in vitamin E deficiency and resultant neurological symptoms—most strikingly a Friedreich-like ataxia (Harding et al. 1985). Vitamin E supplementation slows progression of the disease or may even lead to some improvement of neurological symptoms (Gabsi et al. 2001; Mariotti et al. 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: "Genomic medicine" refers to the diagnosis, optimized management, and treatment of disease--as well as screening, counseling, and disease gene identification--in the context of information provided by an individual patient's personal genome. Genomic medicine, to some extent synonymous with "personalized medicine," has been made possible by recent advances in genome technologies. Genomic medicine represents a new approach to health care and disease management that attempts to optimize the care of a patient based upon information gleaned from his or her personal genome sequence. In this review, we describe recent progress in genomic medicine as it relates to neurological disease. Many neurological disorders either segregate as Mendelian phenotypes or occur sporadically in association with a new mutation in a single gene. Heritability also contributes to other neurological conditions that appear to exhibit more complex genetics. In addition to discussing current knowledge in this field, we offer suggestions for maximizing the utility of genomic information in clinical practice as the field of genomic medicine unfolds.
    Human Genetics 05/2011; 130(1):103-21. DOI:10.1007/s00439-011-1001-1 · 4.82 Impact Factor
  • Source
    • "In this study, knockout mice fed with normal diet of vitamin E did not show early after infection stressing that one of the reasons of inhibition of parasite proliferation in the knockout mice is clearly related to oxidative damage of the parasite. This suggests that knockout mice might possess additional mechanisms to keep normal levels of vitamin E in the RBC membranes [30]. It is impressive that α-TTP knockout mice survived with rising levels of parasitaemia at the later stage of the infection. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Various factors impact the severity of malaria, including the nutritional status of the host. Vitamin E, an intra and extracellular anti-oxidant, is one such nutrient whose absence was shown previously to negatively affect Plasmodium development. However, mechanisms of this Plasmodium inhibition, in addition to means by which to exploit this finding as a therapeutic strategy, remain unclear. alpha-TTP knockout mice were infected with Plasmodium berghei NK65 or Plasmodium yoelii XL-17, parasitaemia, survival rate were monitored. In one part of the experiments mice were fed with a supplemented diet of vitamin E and then infected. In addition, parasite DNA damage was monitored by means of comet assay and 8-OHdG test. Moreover, infected mice were treated with chloroquine and parasitaemia and survival rate were monitored. Inhibition of alpha-tocopherol transfer protein (alpha-TTP), a determinant of vitamin E concentration in circulation, confers resistance to malarial infection as a result of oxidative damage to the parasites. Furthermore, in combination with the anti-malarial drug chloroquine results were even more dramatic. Considering that these knockout mice lack observable negative impacts typical of vitamin E deficiency, these results suggest that inhibition of alpha-TTP activity in the liver may be a useful strategy in the prevention and treatment of malaria infection. Moreover, a combined strategy of alpha-TTP inhibition and chloroquine treatment might be effective against drug resistant parasites.
    Malaria Journal 04/2010; 9(1):101. DOI:10.1186/1475-2875-9-101 · 3.11 Impact Factor
  • Source
    • "Kontush et al. [59] found that reduction of Cu 2 + is more efficient when the levels of a-TOH in LDL are higher, hence implying the role of vitamin E in the initiation of LDL oxidation . This was shown using LDL prepared from plasma of a patient with a familial isolated vitamin E (FIVE) deficiency syndrome, whose levels of circulating a-TOH are 10-to 20-fold lower than those found in healthy humans [60]. This has implications for a pro-oxidant role of a-TOH (cf. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Atherosclerosis is a disease involving both oxidative modifications and disbalance of the immune system. Vitamin E, an endogenous redox-active component of circulating lipoproteins and (sub)cellular membranes whose levels can be manipulated by supplementation, has been shown to play a role in the initiation and progression of the disease. Recent data reveal that the activities of vitamin E go beyond its redox function. Moreover, it has been shown that vitamin E can exacerbate certain processes associated with atherogenesis. In this essay we review the role of biology of atherosclerosis, and suggest that these two facets decide the clinical manifestation and outcome of the disease.
    Atherosclerosis 09/2001; 157(2):257-83. DOI:10.1016/S0021-9150(00)00741-3 · 3.99 Impact Factor
Show more