Tocopherols circulating in lipoproteins can be taken up by tissues via various receptor-mediated processes. Chylomicron remnants are taken up by the parenchymal cells of the liver via an apolipoprotein E–mediated mechanism, and LDL particles are taken up by liver and other tissues via apolipoprotein B100–mediated processes. Other mechanisms of cell uptake may involve selective uptake from HDLs via scavenger receptors, as is the case with cholesterol. In addition, some of the vitamin E in association with chylomicrons and VLDLs may be transferred to peripheral cells during the lipolysis of these triacylglycerol-rich lipoproteins by lipoprotein lipase. Studies of vitamin E delivery to tissues in transgenic mice overexpressing human lipoprotein lipase in muscle demonstrated enhanced vitamin E uptake by skeletal muscle but not by adipose tissue or brain (Sattler et al., 1996). (See Chapter 17 for an overview of lipoprotein metabolism.) The process of secretion of α-tocopherol from the liver via VLDLs is crucial to maintaining normal plasma vitamin E levels. A tocopherol-binding protein, called α-tocopherol transfer protein (α-TTP) plays an essential role in this process. This soluble protein is found predominantly in liver, and preferentially binds RRR-α-tocopherol relative to other forms of vitamin E (Manor and Morley, 2008). It is only one of two proteins known to bind vitamin E with high affinity; the other is cytochrome P450-4F2, as discussed later. α-TTP exhibits two unique properties: high affinity binding of α-tocopherol, and transfer of α-tocopherol from one membrane to another in a process involving direct membrane interaction (Morley et al., 2008). In the liver, α-TTP facilitates the secretion of α-tocopherol into the plasma lipoprotein pool (Traber et al., 1993) via a non–Golgi-dependent mechanism that has not been fully elucidated (Kaempf-Rotzoll et al., 2003). α-TTP has been reported to associate with lysosomes or late endosomes, where it presumably binds and transfers predominantly α-tocopherol to another vesicular compartment for translocation to the cell surface. The ATP-binding cassette transporter A1 (ABCA1), which lipidates apoA1 and lipid-poor HDL with phospholipid and cholesterol, has been reported to facilitate the secretion of vitamin E from cells (Oram et al., 2001; Qian et al., 2005), but a physical interaction between α-TTP and ABCA1 in the liver has yet to be demonstrated. This process contributes to the preferential enrichment of LDLs and HDLs with α-tocopherol compared with the other forms of vitamin E. A critical role for α-TTP in maintaining normal plasma tocopherol concentration has been demonstrated in patients with familial ataxia with isolated vitamin E deficiency, or AVED (Gotoda et al., 1995; Ouahchi et al., 1995; Kayden and Traber, 1993). These patients have clear signs of vitamin E deficiency (extremely low plasma vitamin E and neurological abnormalities) but have no fat malabsorption or lipoprotein abnormalities. Absence of functional α-TTP in these patients impairs secretion of α-tocopherol from liver into the bloodstream, resulting in very low concentrations of plasma vitamin E. Presumably the α-tocopherol not secreted into the bloodstream is secreted into the bile. The plasma vitamin E level of AVED patients can be normalized with high-dose vitamin E supplementation. Tocopherols and tocotrienols other than α-tocopherol undergo extensive postabsorptive metabolism to water-soluble metabolites that are excreted primarily in the urine. This catabolic process involves severe truncation of the hydrophobic phytyl side chain, the moiety responsible for the fat-solubility of vitamin E. The metabolic pathway is depicted in Figure 29-2 and involves an initial hydroxylation of a terminal methyl group (ω-hydroxylation) of the phytyl side chain. In human beings, the enzyme cytochrome P450-4F2 (CYP4F2), an endoplasmic reticulum enzyme that requires NADPH and is expressed predominantly in the liver, has been implicated in this reaction (Sontag and Parker, 2002). The hydroxylated intermediate is further oxidized, apparently by an NAD-dependent dehydrogenase, to the corresponding ω-carboxychromanol. Truncation of the phytyl side chain subsequently occurs by sequential removal of two- or three-carbon units, ultimately yielding the 3′-carboxyethylhydroxychromanol (CEHC) (see Figure 29-2). Despite the relatively high water solubility of these short-chain metabolites, they appear to be largely conjugated with glucuronic acid by the action of uridine 5′-diphospho-glucuronosyltransferase, presumably at the phenolic hydroxyl group, to further facilitate their excretion in urine. α-Tocopherol is a relatively poor substrate for this catabolic pathway, whereas other tocopherols and the tocotrienols are good substrates (Sontag and Parker, 2007). Therefore the tocopherol-ω-oxidation pathway is considered to play a central role in the selective tissue deposition of α-tocopherol via the preferential elimination of the other forms of vitamin E, resulting in the “α-tocopherol phenotype.” This phenotype is widely expressed in the animal kingdom. Though α-TTP also contributes to this phenotype (Figure 29-3), it does not appear to be essential, because the fruit fly, Drosophila, expresses the α-tocopherol phenotype and a cytochrome P450–mediated ω-oxidation pathway similar to that of mammals, yet does not express a protein with the hallmark activity of α-TTP (Parker and McCormick, 2005). To date ω-oxidation is the only known pathway of vitamin E metabolism.
Vitamin E
Absorption, Transport, and Metabolism of Vitamin E
Plasma Transport and Tissue Uptake
Hepatic Secretion and the Role of α-Tocopherol Transfer Protein
Metabolism of Vitamin E and the Role of CYTOCHROME P450-4F2
Vitamin E
