Vitamin E

8 forms of Vitamin E

Vitamin E is a collective term for eight naturally occurring compounds, four tocopherols (α-, β-, γ- and δ-) and four tocotrienols (α-, β-, γ- and δ-), that qualitatively exhibit the biological activities of α-tocopherol. The eight forms of vitamin E are not interconvertible in humans. (R4)

Tocopherols

alpha-Tocopherol

After 2 mo of pill taking, α-tocopherol supplementation increased serum α-tocopherol concentration compared with placebo, but significantly reduced serum γ-tocopherol concentration (R4)

beta-Tocopherol

delta-Tocopherol

In vitro data suggest a health benefit of δ-tocopherol, which has stronger antiproliferative effects on preneoplastic and neoplastic mouse mammary epithelial cells than α- and γ-tocopherol (13). (R4)

gamma-Tocopherol

γ-Tocopherol is more effective than α-tocopherol in inhibiting prostate cancer cell growth (3), reducing oxidative DNA damage (4), increasing superoxide dismutase activity (5) and scavenging mutagenic electrophiles such as peroxynitrite, a potent nitrating and oxidizing compound (6,7). In addition, γ-tocopherol and its major metabolite exhibit greater anti-inflammatory effects than α-tocopherol (8).

The potential benefit of γ-tocopherol is further supported by some epidemiologic studies that documented inverse relationships between serum concentration of γ-tocopherol and coronary heart disease or the risk of developing prostate cancer (9–12). (R4)

Tocotrienols

alpha-Tocotrienol

beta-Tocotrienol

delta-Tocotrienol

gamma-Tocotrienol

Inhibits NLRP3

γT3 repressed inflammasome activation, caspase-1 cleavage, and interleukin (IL) 1β secretion in murine macrophages, implicating the inhibition of NLRP3 inflammasome in the anti-inflammatory and antipyroptotic properties of γT3. Furthermore, supplementation of leptin-receptor KO mice with γT3 attenuated immune cell infiltration into adipose tissue, decreased circulating IL-18 levels, preserved pancreatic β-cells, and improved insulin sensitivity. Mechanistically, γT3 regulated the NLRP3 inflammasome via a two-pronged mechanism: 1) the induction of A20/TNF-α interacting protein 3 leading to the inhibition of the TNF receptor-associated factor 6/nuclear factor κB pathway and 2) the activation of AMP-activated protein kinase/autophagy axis leading to the attenuation of caspase-1 cleavage. Collectively, we demonstrated, for the first time, that γT3 inhibits the NLRP3 inflammasome thereby delaying the progression of type 2 diabetes. This study also provides an insight into the novel therapeutic values of γT3 for treating NLRP3 inflammasome-associated chronic diseases. (R8)

Absorption & Transport

Feed supplements: all-rac-α-tocopheryl acetate or tocopheryl succinate
Absorbed in small intestine as free alcohols or with emulsified fats
Requires bile-activated carboxylic ester hydrolase hydrolysis before absorption
Young animals show limited absorption due to low enzyme activity
Post-absorption: enters circulation via lymphatic system
Packed into chylomicrons with lipids
Transported to liver via chylomicrons and their remnants
No differences between vitamin E forms during transport phase

Source: (R5)

Liver Processing

α-TTP protein crucial for vitamin E metabolism
Selectively maintains α-tocopherol in plasma/tissues
β-, γ-, δ-forms secreted into bile or excreted in feces
Discriminates between 8 stereoisomer forms
2S-forms show minimal bioavailability
α-TTP gene defects lead to:
- Severe vitamin E deficiency
- Neurological disorders
- Lysosomal α-tocopherol accumulation
- Blocked plasma secretion
Species differences in 2R-form discrimination
Species-specific deficiency symptoms:
- Rodents/calves: myocardial necrosis
- Rodents/poultry: encephalomalacia
- Swine: Mulberry heart disease, retinopathia pigmentosa

Source: (R5)

Tissue Distribution

In vitamin E-deficient rats (10 mg/kg all-rac-α-tocopherol injection):
- Plasma: peaks at 3-6h
- RBC: peaks at 12h
- Liver microsomes: peaks at 6h
Correlations:
- Strong RBC-liver mitochondrial fraction (0.85-0.97, p<0.001)
- Strong RBC-liver microsomal fraction (0.75-0.98, p<0.001)
- No correlation with plasma levels
Storage distribution:
- Major storage in mitochondrial/microsomal fractions
- Both inner/outer mitochondrial membranes contain substantial α-tocopherol
- Different intracellular membranes show varying tocopherol-to-lipid ratios
- Varies with polyunsaturated fatty acid content
α-tocopherol hypothesized to concentrate in membrane domains rich in polyunsaturated phospholipids

Source: (R5)

The data furthermore showed that the α-tocopheryl quinone arising from excessive oxidative degradation of α-tocopherol can potentially interfere with mitochondrial electron transfer (R5)

Mitochondrial processing

another metabolite of α-tocopherol, 2,5,7,8-tetramethyl-2(2′-carboxyethyl)-6-hydroxychroman (α-CEHC), was identified.

The metabolites of vitamin E are the CEHC products of the respective forms of vitamin E, that is, α-, β-, γ-, and δ-CEHC, and the various non-α-tocopherol forms are metabolized in preference to α-tocopherol.

Recently, it has been indicated that mitochondria play a role in the metabolism of α-tocopherol, as the end product, α-CEHC, was found almost exclusively in mitochondria.

Thus, mitochondria play a role in α-tocopherol β-oxidation at both basal dietary and high hepatic levels of α-tocopherol. (R5)

Impact on Autophagy, lysosomes and proteasome

Form	Autophagy	Proteasome
Unspecified Tocopherols		No effect on proteasomal activation (R1)
alpha-Tocopherol
delta-Tocopherol
gamma-Tocoherol
Unspecified Tocotrienols	Induction of autophagy (and PSC cell death ☠️) (R7)
alpha-Tocotrienol		Inhibits upregulation of proteasomes in response to insufficient proteasomal activity. Presumably via cancelling NRF1 response (R1)
delta-Tocotrienol		Proteasome inhibitor (R6)
gamma-Tocotrienol	Induces autophagy, increases autolysosomal markers (R8)

Lysosomal processing of vitamin E

Lysosomal enzymes NPC1 and NPC1 appear to be critical for bioavailability of vitamin E:

Vitamin E (α-tocopherol) is the major lipid-soluble antioxidant in many species.

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder caused by mutations in the NPC1 or NPC2 gene, which regulates lipid transport through the endocytic pathway.

NPC disease is characterized by massive intracellular accumulation of unesterified cholesterol and other lipids in lysosomal vesicles.

We examined the roles that NPC1/2 proteins play in the intracellular trafficking of tocopherol. Reduction of NPC1 or NPC2 expression or function in cultured cells caused a marked lysosomal accumulation of vitamin E in cultured cells. In vivo, tocopherol significantly accumulated in murine Npc1-null and Npc2-null livers, Npc2-null cerebella, and Npc1-null cerebral cortices.

Plasma tocopherol levels were within the normal range in Npc1-null and Npc2-null mice, and in plasma samples from human NPC patients. The binding affinity of tocopherol to the purified sterol-binding domain of NPC1 and to purified NPC2 was significantly weaker than that of cholesterol.

Taken together, our observations indicate that functionality of NPC1/2 proteins is necessary for proper bioavailability of vitamin E and that the NPC pathology might involve tissue-specific perturbations of vitamin E status. (R2)

Induction of autophagy

Our results showed for the first time that at least in part, the cardioprotection (evidenced from the ventricular performance, myocardial infarct size and cardiomyocyte apoptosis) with resveratrol and γ-toctrienol was achieved by their abilities to induce autophagy.

Most importantly, resveratrol and γ-tocotrienol acted synergistically providing greater degree of cardioprotection simultaneously generating greater amount of survival signal through the activation of Akt-Bcl-2 survival pathway.

Autophagy was accompanied by the activation of Beclin and LC3-II as well as mTOR signalling, which were inhibited by either 3-methyl adenine (3-MA) or Wortmannin. The autophagy was confirmed from the results of transmission electron microscopy and light microscopy as well as with confocal microscopy. (R7)