Vitamin A - a scoping review for Nordic nutrition Recommendations 2023

Abstract

Vitamin A refers to a group of fat-soluble compounds with retinol activity, including all-trans retinol and pro-vitamin A carotenoids. Bioactive compounds include retinal and all-trans retinoic acid with important functions in vision, immune function, growth, and development. The literature search that was performed for the current scoping review yielded a total of seven publications relevant to setting the recommended daily intake for vitamin A. In total, six publications assessed the relationship of serum retinol and/or dietary vitamin A intake with fracture risk (n = 2), cancer (n = 3), and deficiency after bariatric surgery (n = 1). One additional report by the European Food Safety Administration (EFSA) with updated average requirements was included. The outcomes-based systematic reviews and meta-analyses showed positive associations for vitamin A intake and serum retinol with risk of hip fracture. Weak or inconclusive associations were observed for cancer or obesity. One publication by EFSA with updated estimated average requirements and population reference intakes for dietary vitamin A intakes was published in 2015. The EFSA recommendations and estimated average requirements are based on a European reference population, with body weights derived from an assumed body mass index of 22, which might be too low and not representative of the Nordic and Baltic populations, and consequently resulting in lower estimated average requirements and recommendations. In conclusion, there were limited new outcomes-based data for vitamin A and health outcomes.

Keywords: carotenoids; dietary recommendations; retinol; retinol equivalents; vitamin A.

Fig. 1

In the intestinal lumen, retinyl esters are converted to retinol by REH (retinyl ester hydrolase). Retinol and β-carotene in the intestine is taken up by enterocytes where retinol bound to CRBP2 (cellular retinol-binding protein 2) is converted to retinyl esters through LRAT (lecithin:retinol acyltransferase) and packed in chylomicrons. β-carotene in enterocytes is either packed in chylomicrons or converted to retinal through BCO1 (β-carotene 15,15´-dioxygenase); retinal bound to CRBP2 is then converted to retinol through DHRS3 (NADPH-dependent dehydrogenase reductase 3) and subsequently to retinyl esters through LRAT and stored in chylomicrons. As a feedback mechanism, ATRA is formed from retinal through a two-step process by RALDHs (retinal dehydrogenases) to induce the expression of ISX (intestinal-specific homeobox gene) which inhibits uptake of β-carotene through SCARB1 (scavenger receptor class B type 1) and the conversion to retinal through BCO1. Chylomicrons are released into lymphatics and subsequently to the blood. Circulating retinyl esters present in chylomicrons and bound to lipoproteins are taken up by liver cells where it is either stored in stellate cells or converted to retinol and bound to RBP4 (retinol binding protein 4) and TTR (transthyretin). In the liver cells, β-carotene in chylomicrons and bound to lipoproteins are taken up by CD36 and SCARB1 and subsequently converted to retinal by BCO1 and then to retinol through DHRS3. Retinol is then either converted to retinyl esters to be stored in stellate cells or bound to RBP4 and TTR to be released to the blood. Retinol released from the liver is present in the circulation as retinol bound to RBP4.

Fig. 2

In target cells, retinol is taken up through STRA6 (stimulated by retinoic acid 6) and bound to CRBP1 (cellular retinol-binding protein 1) and subsequently oxidized to retinal by RDH (retinol dehydrogenase). Retinyl esters present in chylomicrons and lipoproteins are taken up and also serve as cellular source for conversion to retinol and retinal. In addition, β-carotene in chylomicrons and lipoproteins is taken up through CD36 and SCARB1 (scavenger receptor class B type 1) and then converted to retinal by BCO1 (β-carotene 15,15´dioxygenase). Retinal is finally metabolized by two different RALDHs (retinal dehydrogenases) to ATRA. ATRA bound to CRABP2 (cellular retinoic acid binding protein 2) is shuttled to the nucleus and then ligated to retinoic acid receptors (RARs). ATRA can also be bound to FABP5 (fatty acid-binding protein 5) and is then ligated to PPAR (peroxisome proliferator-activated receptorβ/δ). Both RARs and PPARβ/δ heterodimerize with retinoic X receptors (RXRs). These complexes cause activation or repression of gene transcription through RARE (retinoic acid response elements) or PPRE (PPAR response elements), respectively.