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.