Transport vitamínu E krví - k játrům, v játrech a z jater

Chilomikra z GIT v cirkulaci

Lipoprotein lipase (LPL)

• Extra-hepatic tissues may take up part of the alpha-tocopherol transported in chylomicrons

Remnant chylomicrons

• Transport alpha-tocopherol to the liver (Traber, 2007; Wu and Croft, 2007; Gee, 2011) [2]
• Most of the VE remains in the chylomicron particle during triglyceride lipolysis by lipoprotein lipase (LPL) [8]

Receptory pro vstup vit. E do jater

ApoB receptor

• Facilitates VE internalization when remnant chylomicrons are directed to the liver [8]

Low-density lipoprotein (LDL) receptor (LDLR)

Lipoprotein-related proteins (LRP)

SR-B1

• VE associated with HDL particles is imported into the liver owing to SR-B1 [8]
• Multi-ligand membrane receptor
• Extensively expressed in many mammalian cell types
• Enterocytes,
• Myocytes,
• Endothelial cells,
• Adipocytes,
• Macrophages
• Only known bidirectional integral membrane protein in the apical site of enterocytes [8]
• Acts as a plasma membrane receptor for high-density lipoprotein cholesterol (HDL)
• Mediates cholesterol transfer to and from HDL
• SR-B1 is involved in the uptake of:
• The main forms of VE from the diet
• Transport from the basolateral site of enterocytes to the blood
• Liver uptake of VE is carried out by SR-B1
• Uptake of VE vitamers–HDL complexes by different acceptor tissues
• Excretion of alpha-tocopherol with biliary secretion [8]
• SR-B1 deficiency results in hypercholesterolemia [8]

Vazba na alpha-tocopherol transfer protein - alpha-TTP v hepatocytech

• Alpha-tocopherol transfer protein (alpha-TTP)
• Preferentially binds alpha-tocopherol rather than other tocopherols or tocotrienols
• Alpha-tocopherol is transferred to hepatocytes (78 % of ingested dose) [2]
• Binds RRR-alpha-tocopherol with the highest affinity (ostatní nenavázané stereoizomery jsou odbourány)
• Responsible for the incorporation of this stereoisomer into nascent very low-density lipoproteins (VLDL)
• For its preferential distribution to peripheral tissues (Traber and Kayden, 1989; Traber et al., 1992; Traber et al., 1994; Stocker and Azzi, 2000; Manor and Morley, 2007; Mustacich et al., 2007)
• To be secreted by the liver into the circulation
• Distributed to body tissues [2]

• VE is not transformed into bioactive forms in enterocytes or along systemic transport
• Bound by alpha-TTP (alpha-tocopherol transfer protein)
• Protecting its side-chain oxidation
• Facilitating VE transfer to liver nascent lipoproteins
• The remaining forms of VE may undergo -hydroxylation by cytochrome P450-mediated metabolism [8]

• Alpha-tocopherol bound to alpha-TTP is not catabolised in the liver by the liver omega-hydroxylase
• Has a stronger activity towards tocopherols other than alpha-tocopherol
• Play critical roles in controlling the metabolism of alpha-tocopherol [2]
• Determining the circulating concentrations of the various tocopherols and tocotrienols
• Limiting alpha-tocopherol accumulation in tissues (Traber, 2007; Wu and Croft, 2007; Traber, 2013).

Zvýšení alpha-TTP gene expression

Oxidative stress

• May increase (Ulatowski et al., 2012) [8]
• Hypoxie [8]
• Via the transcription factor cAMP response element-binding (CREB)[8]

Málo vit. E

• May be hypothesised that hepatic alpha-TTP may increase with decreasing alpha-tocopherol intake [2]
• In rats, a diet deficient in alpha-tocopherol
• Induces lower alphaTTP levels in the liver [8]

Stereoizomery vit. E

Druhy

• Humans discriminate between RRR- and SRR-alpha-tocopherol stereoisomers:
• After intake of equal amounts of D6-RRR-alpha-tocopheryl and D3-SRR-alpha-tocopheryl acetates
• Chylomicrons contained similar concentrations of both forms

Distribuce

• VLDL, LDL and HDL were preferentially enriched in RRR-alpha-tocopheryl acetate (Traber et al., 1990)
• Rate of disappearance of SRR-alpha-tocopherol from plasma
• Was similar to that of RRR-gamma-tocopherol
• Significantly quicker than that of RRR-alpha-tocopherol, after intake of
• D6-RRR-alpha-tocopheryl acetate,
• D3-SRR-alpha-tocopheryl acetate and D2-RRR-gamma-tocopherol (Traber et al., 1992) [2]

Hepatic outflow of HDL

• cholesterol and phospholipids onto apolipoprotein A-1 (Apo-AI)
• Forming nascent high-density lipoprotein (HDL) particles [8]
• Tangier disease’s patients
• Deficiency of the ABCA1 gene
• Absence of serum HDL, hypertriglyceridemia, and reduction in LDL serum levels
• Ectopic accumulation of cholesteryl esters
• Higher incidence of coronary heart and artery disease [8]

Sekrece VE játry do VLDL částic

• Secreted from hepatocytes to plasma lipoproteins (75 % of ingested dose) (zpět do cirkulace) [2]
• VLDL are converted by the action of LPL into:
• Intermediate-density lipoproteins (IDL)
• Low-density lipoproteins (LDL)
• Excess of VLDL surface components, including alpha-tocopherol
• Is transferred to high-density lipoproteins (HDL) (Traber, 2007; Wu and Croft, 2007; Gee, 2011) [2]

Nosiče a formy VE v krvi

Chylomicrons

APOA5

• Apoliporotein A5
• Regulace chylomikronů a TAG plazm.
• Ovlivňuje i hladinu vit. E v plazmě
• Constitutes a minor apolipoprotein
• Almost exclusively expressed in liver
• Found in plasma at low concentrations
• Intracellularly in association with lipid droplets
• Seems to participate in intracellular triglyceride regulation
• Potent regulator of triglyceridemia
• Human deficiency leads to hypertriglyceridemia
• Participates in the assembly of VLDL
• Found in HDL and chylomicrons
• But not in LDL [8]
• Main role in interaction with LPL
• promoting chylomicron clearance
• Decreasing circulating triglycerides [8]
• Obese and diabetic individuals have lower plasma levels of Apo-AV
• In comparison with healthy subjects [8]
• insulin is a negative regulator of the APOA5 gene [8]
• Genetic variants associated with APOA5 in the
• Modulation of lipid metabolism
• Increased risk of obesity and metabolic syndrome

Very low-density lipoprotein (VLDL)/LDL uptake

• VLDL leaves the liver enriched in alpha-tocopherol (cca 65 molecules per particle) [8]

LDL vzniklé z VLDL

• Subsequent conversion to LDL gives alpha-tocopherol-enriched LDL particles (cca 8-12 molecules per particle) [8]

LDL synthesized by the liver

• Is believed that provides other tissues with VE [8]

HDL contains less than one alpha-tocopherol per particle [8]

Mechanismus vstupu VE do extrahepatálních tkání

LPL

• Release during the hydrolysis of triglyceride-rich lipoproteins [8]
• LPL product ::8]
• In extrahepatic tissues, VE is internalized and mixed with triglycerides by the action of lipoprotein lipase (LPL) [8]

LDL receptor pathway

• Delivers to the cells the major part of alpha-tocopherol (Traber and Kayden, 1984)
• Deficiency in the receptor does not lead to a phenotype of alpha-tocopherol deficiency
• Receptor uptake of LDL- and HDL-bound alpha-tocopherol (Traber and Kayden, 1984; Rigotti, 2007; Parks et al., 2000)

Specific receptors

• [8]

Patients with homozygous familial hypercholesterolaemia

• Do not manifest any biochemical or clinical evidence of alpha-tocopherol deficiency (Traber and Kayden, 1984)
• Other mechanisms are likely to be active (Rigotti, 2007) [2]

SR-B1

• Uptake of VE vitamers–HDL complexes by different acceptor tissues

Extrahepatálních tkáně

• Plasma lipoproteins distribute and exchange alpha-tocopherol with three main compartments
• Highest rate of transfer of alpha-tocopherol is between plasma lipoproteins and a multi-organ compartment
• Hepatic stellate cells
• Brain
• Spleen [2]

• Exchange flow and the net flux from plasma lipoproteins to this multi-organ compartment
• Estimated to be about 84 and 3 mg/day [2]

Červené krvinky

• Exchange flow and the net flux from RBC to plasma lipoproteins
• Estimated 19 and 0.1 mg/day [2]

Tuk

• Exchange flow and the net flux from the adipose tissue to plasma lipoproteins
• Estimated 45 and 0 mg/day [2]
• Very large compartment size of the adipose tissue
• Flow was achieved with a very small fractional transfer rate of 0.4 ± 0.1 % of the pool per day [2]

Human alpha-tocopherol associated protein (hTAP)

• Encoded by SEC14L2 gene
• Ubiquitously expressed [8]
• Binds cytosolic alpha-tocopherol
• Contributes to its translocation to the nucleus
• Able to modulate gene expression [8]
• To other organelles such as mitochondria
• Contributes to the maintenance of the oxidative balance of membrane lipids
• Protects from reactive oxygen species [8]
• Few polymorphisms in SEC14L2
• Associated with slightly higher serum concentrations among men carrying the two copies of the variant
• In comparison with the common allele
• Modest serum response to VE supplementation has also been observed [8]

Placenta

• The presence of alpha-TTP in the placenta has been shown (Kaempf-Rotzoll et al., 2003; Muller-Schmehl et al., 2004)
• Immunohistochemical localisation of alpha-TTP and estimated staining intensity
• Alpha-TTP expression in the placenta doubled from the first trimester (six to eight weeks) to term (Rotzoll et al., 2008). [2]

• In an RCT (Pressman et al., 2003), pregnant women received from week 35 of gestation
• Daily prenatal 120 mg vitamin C and 30 IU ‘vitamin E’ - equivalent to 20.1 mg/day of alpha-tocopherol
• With or without additional 500 mg vitamin C and ‘vitamin E’ 400 IU = 268 mg/day of alpha-tocopherol
• Mean maternal plasma alpha-tocopherol concentrations were
• 31.3 micromol/L and 50.4 micromol/L at delivery in each group
• Cord plasma alpha-tocopherol at delivery was only 6.97 micromol/L in both groups (not statistically significant)
• Maternal plasma and chorioamnion alpha-tocopherol concentrations were correlated [2]

• Placenta limits alpha-tocopherol transfer to the fetus (Didenco et al., 2011)
• No significant correlation between maternal and cord blood alpha-tocopherol concentrations
• But a significant correlation was observed between maternal and cord blood alpha-CEHC concentrations
• Mean concentration of umbilical cord blood alpha-CEHC (30.2 ± 28.9 nmol/L) was not significantly different from maternal alpha-CEHC concentration. [2]

• Placental transfer of alpha-tocopherol is relatively constant throughout gestation
• Mean alpha-tocopherol concentration was 9.2 ± 3.3 micromol/L in samples from 13 fetuses with a gestational age up to 22 weeks
• 9.2 ± 4.9 micromol/L in 12 fetuses at 23–27 weeks of gestation
• 8.6 ± 4.2 micromol/L in 27 fetuses with a gestational age of 28–38 weeks [2]
• No significant differences in plasma alpha-tocopherol concentrations in samples from early, mid or late gestation in either the mother or the fetus
• Alpha-tocopherol concentration of cord blood is much lower than that of maternal blood [2]

Z tkání do jater

• Extrahepatic tissues can also provide VE to the liver by reverse cholesterol transport [8]

ABCG1

• ABC family
• Responsible for transfering cholesterol
• From macrophages or vascular endothelial cells to mature HDL particles
• Represent a large fraction of overall plasma HDL
• ABCG1 is responsible for the reverse cholesterol pathway
• Critical for lipid clearance and the transfer of excess cholesterol from peripheral tissues back to the liver [8]
• Participate in vitamin E efflux from cells
• Targeted ABCA1 inactivation in mice
• Decreased levels of HDL as well as VE in plasma [8]
• ABCG1, it has a general impact on VE repartition within the organism
• Its repression induces
• Decreased efflux from cells to HDL
• VE accumulation in tissues as seen in knockout animals [8]

Suprese ABCG1

• Greater VE consumption predisposing to the mRNA suppression of ABC transporters
• Associated with higher cardiovascular risk, at least in animal models [8]

Apo-AI

• Gene encoding for Apo-AI clustered on chromosome 11
• With other apolipoproteins (Apo-AIV, Apo-AV, and Apo-CIII) [8]
• Main protein component of nascent and mature HDL
• Synthesized in the
• Liver (80%)
• Small intestine (10%)
• Cofactor for lecithin cholesterol acyltransferase
• Supports cholesterol efflux from tissues [8]
• Allows the movement of VE from the enterocyte into the bloodstream
• Also present in mature HDL particles
• Favors the reverse transport of cholesterol and tocopherol from the tissues to the liver [8]

Apo-AII is the second most abundant protein in HDL [8]

• Takes part in mature HDL particles
• Participates in the transfer of lipophilic substances between HDL and tissues
• Phospholipids [8]
• Alpha-tocopherol [8]

Apo-E

• Multifunctional protein
• Binding, internalization, and catabolism of lipoprotein particles
• Ligand for lipoprotein receptors
• Mediates clearance from the plasma of
• Triglyceride-rich lipoproteins
• Remnant VLDL
• Chylomicron [8]

Apo-B

• Apo-B gene codifies a single transcript that generates a larger protein, Apo-B100
• Found in lipoproteins originating from the liver
• Very Low-Density Lipoprotein (VLDL)
• Intermediate-Density Lipoprotein (IDL)
• Low-Density Lipoprotein (LDL)
• Shorter isoform, exclusively formed in intestine
• Essential for chylomicron assembly Apo-B48
• Apo-B proteins are recognized by the Apo-B receptor
• Crucial for liver HDL (and VE) uptake mediated by the SR-B1 protein.