Retinoids are essential elements in animals and indeed human. They are acquired through dietary intake of vitamin A which consists, mostly, of retinol (Gropper et al., 2008). Retinoids are mainly stored in the liver and are mobilized to tissues through the activity of various transporters such as the retinol binding protein (RBP) and transthyretin (TTR) (Quadro et al., 2004). Vitamin A is involved in many biological processes within the human body. It is required for maintaining vision, immunity, development and growth, and regulating proliferation and differentiation of some cell types (Moise et al., 2007). During normal physiological conditions, retinol is absorbed via lymphatic routs from the intestinal tract, where it undergoes first step in metabolism and is transported to target tissues for uptake and storage by specialised cells (Dew & Ong, 1997).
This system of transport involves proteins such as retinol binding protein (RBP) and transthyretin (TTR) (Yamamotoa et al., 1997). Within plasma circulation, retinoids can exist as various complexes. Retinoic acid (RA) (a metabolite of retinol) for instance, binds albumin while retinol is found to bind RBP and retinyl ester forms a complex with lipoproteins (mainly chylomicrons) (Blaner, 2007). These transporting mechanisms of vitamin A and its metabolites cooperate to maintain the integrity of the transport system to ensure sufficient, but not excessive, amounts of retinoids reach their target tissues (Basu & Basualdo 1999). Other important players within the redinoids transport system are the lecithin-retinol acyltransferase (LRAT) and the cellular retinol-binding protein (CRBP), which are proteins that facilitate formation of retinyl ester. The main role of these enzymes is to maintain tight homeostatic balance of retinol following a high diet intake or during reduced levels of vitamin A (Moiseyev et al., 2003).
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Upon delivery to target tissue, retinol is taken up into cells through the retinol uptake system. This system of transport involves the activity of plasma transmembrane proteins, such as CBRP, which facilitate the uptake of retinol into cells (Ottonello et al., 1987). The entry of retinol into cells was thought as a simple diffusion process that occurs upon delivery by RBP (mentioned by Kawaguchi et al., 2007). The suggestion of an active uptake mechanism and the existence of a transmembrane transporter for retinol was described by several research groups as early as the 1970s (Heller, 1975), but it was not until recently that this transmembrane transporter was identified as the stimulated by retinoic acid 6 (STRA6) receptor by Kawaguchi et al. (2007). These findings provided a new area of research towards targeting the uptake of retinol in potential therapies.
RETINOIDS TRANSPORT TO TARGET TISSUES
The role of chylomicrons in transporting retinyl ester
Chylomicrons are metabolized in the lymphatic system to form chylomicron remnants. Chylomicrons (Nascent chylomicrons) enter the system through thoracic duct where they are converted to remnants through the activity of lipoprotein lipase (LPL) (Redgrave 2004). Hydrolysis of chylomicron triglycerides by the LPLs to free fatty acids (FFA) facilitate remnant uptake by liver. This is due to the involvement of apolipoproteins (apolipoprotein E, apoE) in regulating receptor-mediated uptake into the liver (Cooper 1997). Chylomicrons containing retinyl esters are taken up, mostly, by the liver. In the liver, retinyl esters from chylomicrons can be stored in lipocyte cells or secreted back as retinol bound to RBP into the circulation (Goodman 1965). The remaining retinyl ester molecules that were not stored nor resecreted by the liver are taken up by various tissues such as adipose tissue, muscles, bone marrow and reproductive system. This clearance of chylomicron-retinoids by extrahepatic tissue is also thought to be facilitated through LPL allowing uptake of whole particles by cells (Bennekuma 1999). The chylomicron-source of retinoids is an important pathway in maintaining target tissues requirements. This importance is noticed, particularly, in RBP deficient mice where mild vision impairment only occurs (Quadro et al 1999). Unless deprivation of vitamin A dietary intake occurs, RBP deficient mice will be phenotypically normal. They can maintain adequate levels of dietary vitamin A but are unable to mobilize liver-stored and tissue-stored retinyl ester. Vitamin A deficiency (VAD) appears to be affecting mice with relatively lower vitamin A intake than those with normal dietary vitamin A intake levels (Vogel et al 2002). Therefore, chylomicrons are important sources of retinoids that can compensate to some extent for the activity of RBP.
Circulation of retinol in plasma mediated by RBP
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The unesterified form of retinol is transported as retinol bound to RBP in the blood (Kanai et al., 1968). The synthesis and secretion of RBP takes place in the liver and other extra-hepatic tissues such as eye, kidney, lung, heart, spleen and adipose tissue (Soprano et al., 1986). The protein TTR is also synthesised within the liver where it is thought to form a complex with RBP, prior to secretion, in the endoplasmic reticulum (ER) (Bellovinoa et al., 1996). The RBP-TTR complex formation prevents its extensive loss through glomerular filtration (Naylor & Newcomer 1999).
Within the circulation, RBP exist as either bound or unbound to retinol (holo-RBP and apo-RBP, respectively). These forms are required for retinol export from its liver stores.
When retinol-RBP complex reach target cells, retinol dissociates rapidly and enters the cell.
The dissociation rate of retinol does not limit the rate of uptake by cells, which can argue that the involvement of a receptor-mediated transport is unnecessary.
However, other studies showed evidence supporting the existence of a multispanning membrane receptor (STRA6) involved in mediating the uptake of retinol, from the retinol-RBP, into target cells.
The newly discovered STRA6 receptor was found to be expressed, in addition to retinal pigmented epithelium, in various blood-organ barriers. Such barriers include choroids plexi yolk sac, and Sertoli cells.
In addition to its role in retinol uptake, the STRA6 receptor is thought to play a crucial role in development and cell differentiation. Mutations in the STRA6 gene were shown to cause several defects including anophthalmia, lung hypoplasia, diaphragmatic hernia, congenital heart defects and mental retardation.
In case of RBP dysfunction, the delivery of retinoid by RBP can by compensated through the activity of chylomicrons while maintaining adequate vitamin A intake, except in the eye.
Therefore, the eye may be considered to mainly rely on STRA6 receptor-mediated uptake of retinol. Furthermore, it can be suggested that RBP and its cell surface receptor may not be required for retinol uptake.
These suggestions are supported by the fact that retinol-dependent functions are not affected by the absence of RBP except in the eye.
Role of Serum Albumin in transporting Retinoic acid
When compared to retinol and retinyl ester, RA is less hydrophobic and thus cannot be absorbed in chylomicrons. RA is transported, while bound to albumin, via the portal system. This is due to its ability to prevent interaction of RBP with TTR when bound to RBP.
Synthetic analogues of RA are shown to be absorbed through the portal system. The route of absorption can depend on the retinoids' lipoohilicity. Therefore, absorption can occur though nascent chylomicrons or mainly through the portal system. It can be concluded that retinoid route of absorption highly depend on its chemical properties.
During fasting only 0.1-0.4% of all-trans-RA and 13-cis-RA within circulation are bound to albumin. Yet, in well-nourished animal models, this amount of circulating RA vastly contributes to the RA pools. Studies in rat showed that RA pools contribute more than 80% of liver and brain needs of RA, while other tissues acquire 5-30% of their RA from these pools. It can be noticed that all-trans-RA and 13-cis-RA are readily taken up, despite their low levels in circulation, by target cells and tissues.
Therefore, albumin-bound RA transport is an important pathway for providing target tissues with retinoid.
RA dissociates from albumin and crosses through the membrane bilayers in a process similar to retinol. Synthetic RA analogues transported through the albumin pathway is considered to be of a pharmacological significance which mimics natural RA uptake. This can provide greater understanding of the process by which RA enters the cells and thus, form the basis of targeted therapies.
UPTAKE AND STORAGE OF RETINOL
Esterification and storage of retinol facilitated by LRAT
As mentioned before, LRAT plays an important role, as an enzyme, in catalyzing the formation of retinyl ester in various tissues (i.e. eye and liver). Its activity is essential for retinoids accumulation in these tissues. For instance, retinyl esters are mainly stored in the hepatic stellate cells of the liver while visual chromophore production mainly depends on their storage in the RPE.
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The absence of retinyl esters from tissues provide evidence for the importance of LRAT in Lrat-/- mice except in adipose tissue where retinyl ester levels are elevated (2-3 fold) compared to wild-type mice.
Adipocytes are considered as important sites for the accumulation of retinyl ester in the body. They account, along with the liver for most of the retinyl ester storage in the body.
The formation of retinyl ester in adipose tissue does not require canalization by LRAT, while the enzyme which facilitates retiny ester formation is not clearly identified.
The enzyme diacylglycerol acyltransferase 1 (DGAT1) catalyze triglyceride formation from acyl-CoA and diacylglycerol. DGAT1 also catalyzes esterification of acyl-CoA-dependent retinol, exhibiting the activity of acyl-CoA-retinol acyltransferase (ARAT) in vitro. It is still believed however, that other enzymes are involved in the formation of reinyl ester within adipose tissue.