LRAT coordinates the negative-feedback regulation of intestinal retinoid biosynthesis from β-carotene

Ramkumar, Srinivasagan; Moon, Jean; Golczak, Marcin; Lintig, Johannes von

doi:10.1016/j.jlr.2021.100055

Cited by 21 publications

(14 citation statements)

References 50 publications

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“…The all-trans retinol from both sources binds to cellular retinol binding protein 2 (CRBP2). The retinol-CRBP2 complex then interacts with lecithin retinol acyltransferase (LRAT) and converts the retinol into retinyl esters and dissociates with CRBP2 [4][5][6]. These retinyl esters are then packaged into nascent chylomicrons along with other lipids and excreted into general circulation through exocytosis.…”

Section: Mechanisms Involving Intestinal Absorption Of Provitamin a Carotenoids And Preformed Vitamin Amentioning

confidence: 99%

Vitamin A Transporters in Visual Function: A Mini Review on Membrane Receptors for Dietary Vitamin A Uptake, Storage, and Transport to the Eye

et al. 2021

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Vitamins are essential compounds obtained through diet that are necessary for normal development and function in an organism. One of the most important vitamins for human physiology is vitamin A, a group of retinoid compounds and carotenoids, which generally function as a mediator for cell growth, differentiation, immunity, and embryonic development, as well as serving as a key component in the phototransduction cycle in the vertebrate retina. For humans, vitamin A is obtained through the diet, where provitamin A carotenoids such as β-carotene from plants or preformed vitamin A such as retinyl esters from animal sources are absorbed into the body via the small intestine and converted into all-trans retinol within the intestinal enterocytes. Specifically, once absorbed, carotenoids are cleaved by carotenoid cleavage oxygenases (CCOs), such as Beta-carotene 15,15’-monooxygenase (BCO1), to produce all-trans retinal that subsequently gets converted into all-trans retinol. CRBP2 bound retinol is then converted into retinyl esters (REs) by the enzyme lecithin retinol acyltransferase (LRAT) in the endoplasmic reticulum, which is then packaged into chylomicrons and sent into the bloodstream for storage in hepatic stellate cells in the liver or for functional use in peripheral tissues such as the retina. All-trans retinol also travels through the bloodstream bound to retinol binding protein 4 (RBP4), where it enters cells with the assistance of the transmembrane transporters, stimulated by retinoic acid 6 (STRA6) in peripheral tissues or retinol binding protein 4 receptor 2 (RBPR2) in systemic tissues (e.g., in the retina and the liver, respectively). Much is known about the intake, metabolism, storage, and function of vitamin A compounds, especially with regard to its impact on eye development and visual function in the retinoid cycle. However, there is much to learn about the role of vitamin A as a transcription factor in development and cell growth, as well as how peripheral cells signal hepatocytes to secrete all-trans retinol into the blood for peripheral cell use. This article aims to review literature regarding the major known pathways of vitamin A intake from dietary sources into hepatocytes, vitamin A excretion by hepatocytes, as well as vitamin A usage within the retinoid cycle in the RPE and retina to provide insight on future directions of novel membrane transporters for vitamin A in retinal cell physiology and visual function.

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Section: Mechanisms Involving Intestinal Absorption Of Provitamin a Carotenoids And Preformed Vitamin Amentioning

confidence: 99%

Vitamin A Transporters in Visual Function: A Mini Review on Membrane Receptors for Dietary Vitamin A Uptake, Storage, and Transport to the Eye

et al. 2021

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“…The amount of retinol available for RA synthesis within enterocytes is controlled by LRAT. Ablation of Lrat in mice leads to exaggerated feedback due to high levels of available retinol [ 132 ]. It is important to note, that a negative feedback mechanism does not appear to operate in the case of the intestinal uptake of dietary preformed vitamin A (retinol, retinyl esters) which are incidentally are associated with a much higher risk of teratogenicity and toxicity compared to provitamin A carotenoids.…”

Section: Vitamin a Absorptionmentioning

confidence: 99%

Mechanisms of Feedback Regulation of Vitamin A Metabolism

2022

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Vitamin A is an essential nutrient required throughout life. Through its various metabolites, vitamin A sustains fetal development, immunity, vision, and the maintenance, regulation, and repair of adult tissues. Abnormal tissue levels of the vitamin A metabolite, retinoic acid, can result in detrimental effects which can include congenital defects, immune deficiencies, proliferative defects, and toxicity. For this reason, intricate feedback mechanisms have evolved to allow tissues to generate appropriate levels of active retinoid metabolites despite variations in the level and format, or in the absorption and conversion efficiency of dietary vitamin A precursors. Here, we review basic mechanisms that govern vitamin A signaling and metabolism, and we focus on retinoic acid-controlled feedback mechanisms that contribute to vitamin A homeostasis. Several approaches to investigate mechanistic details of the vitamin A homeostatic regulation using genomic, gene editing, and chromatin capture technologies are also discussed.

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“…For preformed vitamin A, the efficiency of absorption is typically around 70%, whereas for carotenoids, it is typically 20–30%, being lower as the ingested dose increases ( 5 , 59 ). A feedback mechanism has recently been described whereby retinoic acid acting as a ligand for RAR induces an inhibitory transcription factor, ISX, that blocks the transcription of the ABCA1 and BCO-1 required for carotene uptake and cleavage, and subsequent retinol esterification ( 60 ).…”

Section: Metabolism Of Dietary Vitamin Amentioning

confidence: 99%

Vitamin A, systemic T-cells, and the eye: Focus on degenerative retinal disease

2022

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The first discovered vitamin, vitamin A, exists in a range of forms, primarily retinoids and provitamin carotenoids. The bioactive forms of vitamin A, retinol and retinoic acid, have many critical functions in body systems including the eye and immune system. Vitamin A deficiency is associated with dysfunctional immunity, and presents clinically as a characteristic ocular syndrome, xerophthalmia. The immune functions of vitamin A extend to the gut, where microbiome interactions and nutritional retinoids and carotenoids contribute to the balance of T cell differentiation, thereby determining immune status and contributing to inflammatory disease around the whole body. In the eye, degenerative conditions affecting the retina and uvea are influenced by vitamin A. Stargardt’s disease (STGD1; MIM 248200) is characterised by bisretinoid deposits such as lipofuscin, produced by retinal photoreceptors as they use and recycle a vitamin A-derived chromophore. Age-related macular degeneration features comparable retinal deposits, such as drusen featuring lipofuscin accumulation; and is characterised by parainflammatory processes. We hypothesise that local parainflammatory processes secondary to lipofuscin deposition in the retina are mediated by T cells interacting with dietary vitamin A derivatives and the gut microbiome, and outline the current evidence for this. No cures exist for Stargardt’s or age-related macular degeneration, but many vitamin A-based therapeutic approaches have been or are being trialled. The relationship between vitamin A’s functions in systemic immunology and the eye could be further exploited, and further research may seek to leverage the interactions of the gut-eye immunological axis.

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LRAT coordinates the negative-feedback regulation of intestinal retinoid biosynthesis from β-carotene

Cited by 21 publications

References 50 publications

Vitamin A Transporters in Visual Function: A Mini Review on Membrane Receptors for Dietary Vitamin A Uptake, Storage, and Transport to the Eye

Vitamin A Transporters in Visual Function: A Mini Review on Membrane Receptors for Dietary Vitamin A Uptake, Storage, and Transport to the Eye

Mechanisms of Feedback Regulation of Vitamin A Metabolism

Vitamin A, systemic T-cells, and the eye: Focus on degenerative retinal disease

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