**1. Introduction**

Vitamin E is a lipophilic vitamin and thus naturally mainly occurring in high-fat plant products such as oils, nuts, germs, seeds, and in lower amounts in vegetables and some fruits. The term "vitamin E" comprises different structures that are classified as tocopherols (TOH), tocotrienols (T3), and "vitamin E-related structures". However, α-TOH is considered as the most important representative of vitamin E in humans as the central vitamin E metabolizing organ, the liver, discriminates for this form [1]. Notwithstanding the classification as vitamin, the way vitamin E exactly contributes to human health is controversially discussed. Vitamin

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

E deficiency has been linked to several disease states like ataxia with vitamin E deficiency (AVED) [2, 3] and Alzheimer's disease [4, 5], indicating a role in the preservation of human health. AVED has severe neurological consequences and is caused by a defect in the α-TOH transfer protein (α-TTP); the protein responsible for the discrimination of α-TOH from the other vitamin E forms in the liver [2, 3]. This emphasizes the role of the liver as a central organ in human vitamin E handling. The liver further distributes vitamin E in the body [6] and metabolizes excess vitamin E in order to form products for excretion [6] or presumably to produce activated metabolites of vitamin E as known for other lipophilic vitamins [7]. Given the crucial role of the liver for vitamin E handling, this review aims to summarize the knowledge on the physiological hepatic handling of vitamin E as well as on factors influencing hepatic handling of vitamin E.

**2.2. Intracellular trafficking of vitamin E**

PI(4,5)P<sup>2</sup>

and PI(3,4)P<sup>2</sup>

of α-TTP: the PI(4,5)P<sup>2</sup>

**2.3. Intracellular storage of vitamin E**

Following its lipophilic nature, vitamin E is transported by intracellular carrier proteins [24]. The intestinally absorbed vitamin E is taken up via endocytosis [25] and follows endosomal fate. Here, the hepatic sorting of vitamin E forms starts as a specific protein, called α-TTP selectively recognizes and preferentially binds α-TOH, which is then extracted from endosomes and transported to the inner leaflet of the plasma membrane [26]. α-TTP is therefore considered to be a "gatekeeper", which discriminates non-α-TOH forms [27] and regulates the plasma concentrations of α-TOH [1]. The affinity of α-TTP to the different forms of vitamin E differs greatly: it is defined as 100% for α-TOH, whereas β-TOH has 38%, γ-TOH 9%, δ-TOH 2%, and α-tocotrienol (T3) 12% affinity to α-TTP [28]. The regular function of α-TTP is crucial, since missense mutations lead to the disruption of α-TOH distribution and the development of a severe degenerative disease, termed AVED [29]. The transfer of α-TOH from endosomes to the plasma membrane is a multi-step process. First, it is speculated whether the ATP-binding cassette transporter A1 (ABCA1) enriches the outer layer of endosomes with α-TOH [30]. The cholesterol transporter NPC1 may also be involved, as a genetic missense mutation of the *NPC1* gene leads to an accumulation of α-TOH in late endosomes [31]. Second, α-TTP extracts the α-TOH from endosomes, and third, α-TTP mediates its transport to the plasma membrane [24]. This process seems to depend on phosphatidylinositol phosphates (PIPs; preferentially

α-TOH to the plasma membrane and stimulating its release [32]. Chung et al. analyzed the localization of α-TTP depending on the cellular α-TOH concentration [33]. They found (i) perinuclear localization for α-TOH-depleted cells, (ii) a directional transport of α-TOH/α-TTP toward the plasma membrane, when depleted cells were pulsed with a low dose of α-TOH, and (iii) a homogenous cytosolic pattern under long-term and high-dose treatment of cells with α-TOH, which was suggested to be the picture of several α-TOH transport cycles [33]. Furthermore, the authors also postulated a bi-phasic concentration-dependent circulation

the α-TTP-mediated transport of α-TOH toward the plasma membrane, whereas the α-TOH gradient (low in plasma membrane and high in endosomes) triggers the recycling of α-TTP toward the endosomes [33]. It has been proposed that once α-TOH is incorporated into the plasma membrane, it is mediated toward the outer leaflet of the membrane by a flippase, maybe ABCA1, and is then available for the uptake via very low density lipoproteins (VLDL)

Intracellular storage of vitamin E is limited to the lipophilic sites of the cell, which are membranes and lipid droplets [33]. Not much is known about a specific localization of vitamin E accumulation in liver cells, apart from the observation that lysosomal membranes of rat livers seemed to have the highest concentration of all membranes [35–37]. However, it is known that one-third of the total body vitamin E is stored in the liver [38]. Within membranes, vitamin E is thought to stabilize the membrane bilayers due to colocalization with phosphatidylcholine [39] and cholesterol (leading to an association to lipid rafts) [40]. It was further hypothesized

[34]. For more details on the process, please see Section 2.5 "Release of vitamin E".

) in the plasma membrane, as α-TTP binds to them, in turn targeting

The Hepatic Fate of Vitamin E

3

http://dx.doi.org/10.5772/intechopen.79445

gradient (low in endosomes and high in plasma membrane) forces
