Retinol Metabolism in Human Liver
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Retinol Metabolism in Human Liver

Vitamin-A (all-trans-Retinol), one of the essential micronutrient in the human is obtained chiefly in form of Retinyl Esters from meat, and Carotenoids, such as Beta-Carotene, from plant tissue. Beta-carotene and other Carotenoids are converted by the body into Retinol and are referred to as Provitamin-A Carotenoids. Hundreds of different Carotenoids are synthesized by plants, but only about 10 percent of them are Provitamin-A Carotenoids (Ref.1). The main site for synthesis and storage of Vitamin-A is in the liver. The pRBPs (Plasma Retinol-Binding Proteins) and Ttr (Transthyretin) facilitate the transfer of insoluble Vitamin-A between tissues, principally from storage sites in the liver to peripheral tissues. In the absence of pRBPs and Ttr the supply of Vitamin-A to target tissues is accomplished via newly absorbed all-trans-Retinyl Esters, or Beta-Carotene that are present in circulating Chylomicrons. Chylomicrons release all-trans-Retinyl Esters due to the catalytic activity of LPL (Lipoprotein Lipase). LPL remains attached to the membrane by a GPI Anchor (Glycophosphatidylinositol Anchor), whose primary function is the hydrolysis of triglycerides of circulating Chylomicrons and VLDLs (Very Low Density Lipoproteins). Vitamin-A is a generic term for a large number of related compounds; Retinol (an Alcohol) and Retinal (an Aldehyde) are often referred to as preformed Vitamin-A. Retinal is converted by the body to Retinoic Acid, the form of Vitamin-A known to affect gene transcription. Mostly the all-trans-Retinoic Acid, the Carboxylic Acid form of Vitamin-A is of biological significance since it has high circulating levels than other isomers of Retinoic Acid. The all-trans form is predominant under most physiological situations and explains all of the biological effects of Vitamin-A. Other forms of Vitamin-A metabolites include Retinyl Esters. However ‘Retinoids’ are Vitamin-A derivatives which cannot substitute for Vitamin-A and some of them even act as Vitamin-A antagonists for which these compounds are collectively known as ‘Retinoate Analogues’ or ‘Vitamin-A Analogues’ (Ref.2 & 3).

Channeling of Vitamin-A and its metabolites between their corresponding binding proteins and a particular protein target is a general theme through which RBPs (Retinol-Binding Proteins) exert their effects. In blood, the ternary complex pRBP-Ttr-Vitamin-A serves to transport Vitamin-A in the circulation and to deliver it to target tissues. Vitamin-A enters Hepatocytes through diffusion in the form of free Vitamin-A, unaccompanied by the binding proteins. In the cyotosol Vitamin-A actively bind to cRBPs (Cellular Retinol-Binding Proteins), thereby the cytosolic concentration of free Vitamin-A decreases. Following uptake of Chylomicrons by the Hepatocytes, all-trans-Retinyl Ester incorporated in these particles are hydrolysed by REH (Retinyl Ester Hydrolase) to yield free Vitamin-A. When excess, Vitamin-A diffuses into Stellate cells, where it is re-esterified by ARAT (Acyl-CoA:Retinol Acyltransferase) and LRAT (Lecithin Retinol Acyltransferase) (Ref.3 & 4). In Vitamin-A deficiency, all-trans-Retinyl Ester, stored in lipid droplets in the Stellate cells, are hydrolysed by REH. Free Vitamin-A thus produced moves back to the Hepatocytes, where it complexes with pRBP, triggering secretion of pRBP into the blood. In the Hepatocytes, Vitamin-A is degraded by Cytochrome P450 enzymes to form Retinol Metabolites. Alternatively, Vitamin-A is oxidized to 11-cis-Retinal by RDH (Retinol Dehydrogenase). 11-cis-Retinal is vital for Visual Cycle in Retinal cells of the human eye. 11-cis-Retinal then binds to CRALBP (Cellular Retinaldehyde-Binding Protein) and is subsequently oxidized to all-trans-Retinoic Acid by RALDH (Retinal Dehydrogenase). Degradation of CRABP (Cellular Retinoic Acid Binding Protein) bound all-trans-Retinoic Acid is catalyzed by specific Cytochrome-P450 CYP26 (Cytochrome P450 Family-26) enzymes. all-trans-Retinoic Acid is further isomerizes into its cis-isoforms. However the physiological significance of this isomerization is yet to be ascertained. cRBPs draw Vitamin-A from blood into the cell by shifting the equilibrium between plasma and cellular Vitamin-A pools. cRBPs also control the formation and hydrolysis of all-trans-Retinyl Esters (Ref.4 & 5).

Vitamin A and its metabolites are critical for vision, play important roles in regulating proliferation and differentiation in both fetal and adult tissues, and are implicated in modulating immune function. Vitamin-A excess and deficiency are known to cause birth defects (Ref.2). Vitamin-A metabolism disorders leads to abnormalities like Night Blindness, Bitots Spots, Xeropthalmia, Corneal Ulcers, Retinal Dystrophies and Dysfunctions, increased susceptibility to Diarrhea and Measles, Retinitis Pigmentosa, Psoriasis, Acute Promyelotic Leukemia, etc to name a few. The condition caused by Vitamin-A toxicity is called Hypervitaminosis-A. It is caused by over consumption of preformed Vitamin-A, not Carotenoids. Significant dietary intake of Vitamin-A however reduce the chances of Cancer in skin, breast, liver, colon, prostate, and other sites. Breakthrough is required for successful treatment of genetic defects in Vitamin-A metabolism in order to prevent or cure many of these diseases (Ref.6).