scholarly journals RDH10 is the primary enzyme responsible for the first step of embryonic Vitamin A metabolism and retinoic acid synthesis

2011 ◽  
Vol 357 (2) ◽  
pp. 347-355 ◽  
Author(s):  
Krysten M. Farjo ◽  
Gennadiy Moiseyev ◽  
Olga Nikolaeva ◽  
Lisa L. Sandell ◽  
Paul A. Trainor ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Acid Synthesis ◽  
Vitamin A Metabolism

scholarly journals Normalization of enzyme expression and activity regulating vitamin A metabolism increases RAR-beta expression and reduces cellular migration and proliferation in diseases caused by tuberous sclerosis gene mutations

2020 ◽  
Author(s):  
ElHusseiny MM Abdelwahab ◽  
Judit Bovari-Biri ◽  
Gabor Smuk ◽  
Tunde Harko ◽  
Janos Fillinger ◽  
...  
Keyword(s):  
Cell Migration ◽  
Retinoic Acid ◽  
Vitamin A ◽  
Tuberous Sclerosis ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Cellular Migration ◽  
Immunofluorescent Staining ◽  
Vitamin A Metabolism ◽  
Expression And Activity

Abstract Background Mutation in a tuberous sclerosis gene (TSC1 or 2) leads to continuous activation of the mammalian target of rapamycin (mTOR). mTOR activation alters cellular including vitamin A metabolism and retinoic acid receptor beta (RARβ) expression. The goal of the present study was to investigate the molecular connection between vitamin A metabolism and TSC mutation. We also aimed to investigate the effect of the FDA approved drug rapamycin and the vitamin A metabolite retinoic acid (RA) in cell lines with TSC mutation. Methods Expression and activity of vitamin A associated metabolic enzymes and RARβ were assessed in human kidney angiomyolipoma derived cell lines, primary lymphangioleiomyomatosis (LAM) tissue derived LAM cell lines as well as RARβ protein levels were tested in primary LAM lung tissue sections. TaqMan arrays, enzyme activities, qRT-PCRs, immunohistochemistry, immunofluorescent staining and western blotting were performed and analysed. The functional effects of retinoic acid (RA) and rapamycin were tested in a scratch and a BrDU assay to assess cell migration and proliferation. Results Metabolic enzyme arrays revealed a general deregulation of many enzymes involved in vitamin A metabolism including aldehyde dehydrogenases (ALDHs), alcohol dehydrogenases (ADHs) and Cytochrome P450 2E1 (CYP2E1). Furthermore, RARβ downregulation was a characteristic feature of all TSC-deficient cell lines and primary tissues. Combination of the two FDA approved drugs -RA for acute myeloid leukaemia and rapamycin for TSC mutation- normalised ALDH and ADH expression and activity, restored RARβ expression and reduced cellular proliferation and migration. Conclusion Deregulation of vitamin A metabolizing enzymes is a feature of TSC mutation. RA can normalize RARβ levels and limit cell migration, but does not have a significant effect on proliferation. Based on our data, translational studies could confirm whether combination of RA with reduced dosage of rapamycin would have more beneficial effects to higher dosage of rapamycin monotherapy meanwhile reducing adverse effects of rapamycin for patients with TSC mutation.

scholarly journals Vitamin A metabolic aspects and alcoholic liver disease

2006 ◽  
Vol 19 (5) ◽  
pp. 601-610
Author(s):  
Tatiana Pereira de Paula ◽  
Wilza Arantes Ferreira Peres ◽  
Rejane Andréa Ramalho ◽  
Henrique Sérgio Moraes Coelho
Keyword(s):  
Retinoic Acid ◽  
Liver Disease ◽  
Vitamin A ◽  
Alcoholic Liver Disease ◽  
Vitamin A Deficiency ◽  
Scientific Evidence ◽  
Acid Synthesis ◽  
Clinical Effects ◽  
Chronic Alcoholic ◽  
Peripheral Tissues

The liver is a strategic organ in the metabolism of macro and micronutrients; when its functioning is compromised, it may cause some change in the nutritional status of vitamin A. The purpose of this article is to review scientific evidence in literature on the liver metabolism of vitamin A, the role of ethanol and retinol interactions on hepatic morphology, besides the alterations in the metabolism of this vitamin in alcoholic liver disease. Data were collected from Medline database. The liver is the main organ responsible for the storage, metabolism and distribution of vitamin A to peripheral tissues. This organ uses retinol for its normal functioning such as cell proliferation and differentiation. This way, vitamin A deficiency seems to alter liver morphology. Patients with alcoholic liver disease have been found to have low hepatic levels of retinol in all stages of their disease. In alcoholic liver disease, vitamin A deficiency may result from decreased ingestion or absorption, reduction in retinoic acid synthesis or increased degradation. Long-term alcohol intake results in reduced levels of retinoic acid, which may promote the development of liver tumor. So, in chronic alcoholic subjects, vitamin A status needs to be closely monitored to avoid its deficiency and clinical effects, however its supplementation must be done with caution since the usual dose may be toxic for those who consume ethanol.

scholarly journals Role and Mechanism of Vitamin A Metabolism in the Pathophysiology of Parkinson’s Disease

2021 ◽  
pp. 1-22
Author(s):  
Anaıs Marie ◽  
Morgane Darricau ◽  
Katia Touyarot ◽  
Louise C. Parr-Brownlie ◽  
Clémentine Bosch-Bouju
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Retinoic Acid ◽  
Vitamin A ◽  
Dopaminergic Neurons ◽  
Potential Role ◽  
Therapeutic Potential ◽  
Vitamin A Metabolism ◽  
Health And Wellbeing

Evidence shows that altered retinoic acid signaling may contribute to the pathogenesis and pathophysiology of Parkinson’s disease (PD). Retinoic acid is the bioactive derivative of the lipophilic vitamin A. Vitamin A is involved in several important homeostatic processes, such as cell differentiation, antioxidant activity, inflammation and neuronal plasticity. The role of vitamin A and its derivatives in the pathogenesis and pathophysiology of neurodegenerative diseases, and their potential as therapeutics, has drawn attention for more than 10 years. However, the literature sits in disparate fields. Vitamin A could act at the crossroad of multiple environmental and genetic factors of PD. The purpose of this review is to outline what is known about the role of vitamin A metabolism in the pathogenesis and pathophysiology of PD. We examine key biological systems and mechanisms that are under the control of vitamin A and its derivatives, which are (or could be) exploited for therapeutic potential in PD: the survival of dopaminergic neurons, oxidative stress, neuroinflammation, circadian rhythms, homeostasis of the enteric nervous system, and hormonal systems. We focus on the pivotal role of ALDH1A1, an enzyme expressed by dopaminergic neurons for the detoxification of these neurons, which is under the control of retinoic acid. By providing an integrated summary, this review will guide future studies on the potential role of vitamin A in the management of symptoms, health and wellbeing for PD patients.

scholarly journals Clickable Vitamins as a New Tool to Track Vitamin A and Retinoic Acid in Immune Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Amelie V. Bos ◽  
Martje N. Erkelens ◽  
Sebastiaan T.A. Koenders ◽  
Mario van der Stelt ◽  
Marjolein van Egmond ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
B Cells ◽  
Vitamin A ◽  
Immune Cells ◽  
Immune Cell ◽  
Human Monocyte ◽  
Valuable Insight ◽  
Vitamin A Metabolism ◽  
Cd38 Expression ◽  
Human Immune

The vitamin A derivative, retinoid acid (RA) is key player in guiding adaptive mucosal immune responses. However, data on the uptake and metabolism of vitamin A within human immune cells has remained largely elusive because retinoids are small, lipophilic molecules which are difficult to detect. To overcome this problem and to be able to study the effect of vitamin A metabolism in human immune cell subsets, we have synthesized novel bio-orthogonal retinoid-based probes (clickable probes), which are structurally and functionally indistinguishable from vitamin A. The probes contain a functional group (an alkyne) to conjugate to a fluorogenic dye to monitor retinoid molecules in real-time in immune cells. We demonstrate, by using flow cytometry and microscopy, that multiple immune cells have the capacity to internalize retinoids to varying degrees, including human monocyte-derived dendritic cells (DCs) and naïve B lymphocytes. We observed that naïve B cells lack the enzymatic machinery to produce RA, but use exogenous retinoic acid to enhance CD38 expression. Furthermore, we showed that human DCs metabolize retinal into retinoic acid, which in co-culture with naïve B cells led to of the induction of CD38 expression. These data demonstrate that in humans, DCs can serve as an exogenous source of RA for naïve B cells. Taken together, through the use of clickable vitamins our data provide valuable insight in the mechanism of vitamin A metabolism and its importance for human adaptive immunity.

scholarly journals Leukocyte Homing, Fate, and Function Are Controlled by Retinoic Acid

2015 ◽  
Vol 95 (1) ◽  
pp. 125-148 ◽  
Author(s):  
Yanxia Guo ◽  
Chrysothemis Brown ◽  
Carla Ortiz ◽  
Randolph J. Noelle
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Immune Cell ◽  
Active Form ◽  
Cell Lineage ◽  
Vitamin A Metabolism ◽  
Immune Cell Subsets ◽  
Development And Differentiation ◽  
And Function ◽  
Leukocyte Homing

Although vitamin A was recognized as an “anti-infective vitamin” over 90 years ago, the mechanism of how vitamin A regulates immunity is only beginning to be understood. Early studies which focused on the immune responses in vitamin A-deficient (VAD) animals clearly demonstrated compromised immunity and consequently increased susceptibility to infectious disease. The active form of vitamin A, retinoic acid (RA), has been shown to have a profound impact on the homing and differentiation of leukocytes. Both pharmacological and genetic approaches have been applied to the understanding of how RA regulates the development and differentiation of various immune cell subsets, and how RA influences the development of immunity versus tolerance. These studies clearly show that RA profoundly impacts on cell- and humoral-mediated immunity. In this review, the early findings on the complex relationship between VAD and immunity are discussed as well as vitamin A metabolism and signaling within hematopoietic cells. Particular attention is focused on how RA impacts on T-cell lineage commitment and plasticity in various diseases.

scholarly journals Retinol, Retinoic Acid, and Retinol-Binding Protein 4 are Differentially Associated with Cardiovascular Disease, Type 2 Diabetes, and Obesity: An Overview of Human Studies

2019 ◽  
Vol 11 (3) ◽  
pp. 644-666 ◽  
Author(s):  
Thomas Olsen ◽  
Rune Blomhoff
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Retinoic Acid ◽  
Vitamin A ◽  
Binding Protein ◽  
Human Studies ◽  
Retinol Binding Protein ◽  
Retinol Binding Protein 4 ◽  
Vitamin A Metabolism

ABSTRACT Vitamin A is a fat-soluble essential nutrient obtained from plant- and animal-based sources that has roles in growth, vision, and metabolism. Vitamin A circulates mainly as retinol bound to retinol-binding protein 4 (RBP4), and is delivered to tissues and converted to retinoic acid, which is a ligand for several nuclear receptors. In recent years, aspects of vitamin A metabolism have been under scrutiny with regards to the development of metabolic and lifestyle diseases including cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and overweight and obesity in humans. Studies have mainly focused on RBP4 in this context, whereas the major circulating form, retinol, and the major bioactive form, retinoic acid, have been overlooked in this regard until recently. As one of the main roles of RBP4 is to deliver retinol to tissues for biological action, the associations of retinol and retinoic acid with these diseases must also be considered. In this review, we summarize and discuss recent and available evidence from human studies with focus on retinol, retinoic acid, and RBP4 and provide an overview of these crucial components of vitamin A metabolism in CVD, T2DM, and obesity. In summary, retinol was found to be both inversely and positively associated with CVD whereas the associations with T2DM and obesity were less clear. Although only a few studies have been published on retinoic acid, it was inversely associated with CVD. In contrast, serum RBP4 was mostly found to be positively associated with CVD, T2DM, and obesity. At present, it is difficult to ascertain why the reported associations differ depending on the compound under study, but there is a clear imbalance in the literature in disfavor of retinol and retinoic acid, which needs to be considered in future human studies.

scholarly journals Normalization of Enzyme Expression and Activity Regulating Vitamin A Metabolism Increases RAR-Beta Expression and Reduces Cellular Migration and Proliferation in Diseases Caused by Tuberous Sclerosis Gene Mutations

2021 ◽  
Vol 11 ◽  
Author(s):  
Elhusseiny Mohamed Mahmoud Abdelwahab ◽  
Judit Bovari-Biri ◽  
Gabor Smuk ◽  
Tunde Harko ◽  
Janos Fillinger ◽  
...  
Keyword(s):  
Cell Migration ◽  
Retinoic Acid ◽  
Vitamin A ◽  
Tuberous Sclerosis ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Cellular Migration ◽  
Immunofluorescent Staining ◽  
Vitamin A Metabolism ◽  
Expression And Activity

BackgroundMutation in a tuberous sclerosis gene (TSC1 or 2) leads to continuous activation of the mammalian target of rapamycin (mTOR). mTOR activation alters cellular including vitamin A metabolism and retinoic acid receptor beta (RARβ) expression. The goal of the present study was to investigate the molecular connection between vitamin A metabolism and TSC mutation. We also aimed to investigate the effect of the FDA approved drug rapamycin and the vitamin A metabolite retinoic acid (RA) in cell lines with TSC mutation.MethodsExpression and activity of vitamin A associated metabolic enzymes and RARβ were assessed in human kidney angiomyolipoma derived cell lines, primary lymphangioleiomyomatosis (LAM) tissue derived LAM cell lines. RARβ protein levels were also tested in primary LAM lung tissue sections. TaqMan arrays, enzyme activities, qRT-PCRs, immunohistochemistry, immunofluorescent staining, and western blotting were performed and analysed. The functional effects of retinoic acid (RA) and rapamycin were tested in a scratch and a BrDU assay to assess cell migration and proliferation.ResultsMetabolic enzyme arrays revealed a general deregulation of many enzymes involved in vitamin A metabolism including aldehyde dehydrogenases (ALDHs), alcohol dehydrogenases (ADHs) and Cytochrome P450 2E1 (CYP2E1). Furthermore, RARβ downregulation was a characteristic feature of all TSC-deficient cell lines and primary tissues. Combination of the two FDA approved drugs -RA for acute myeloid leukaemia and rapamycin for TSC mutation- normalised ALDH and ADH expression and activity, restored RARβ expression and reduced cellular proliferation and migration.ConclusionDeregulation of vitamin A metabolizing enzymes is a feature of TSC mutation. RA can normalize RARβ levels and limit cell migration but does not have a significant effect on proliferation. Based on our data, translational studies could confirm whether combination of RA with reduced dosage of rapamycin would have more beneficial effects to higher dosage of rapamycin monotherapy meanwhile reducing adverse effects of rapamycin for patients with TSC mutation.

scholarly journals Normalization of enzyme expression and activity regulating vitamin A metabolism increases RAR-beta expression and reduces cellular migration in diseases caused by tuberous sclerosis gene mutations

2020 ◽  
Author(s):  
ElHusseiny MM Abdelwahab ◽  
Judit Bovari-Biri ◽  
Gabor Smuk ◽  
Tunde Harko ◽  
Janos Fillinger ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Tuberous Sclerosis ◽  
Treatment Options ◽  
Human Kidney ◽  
Cellular Migration ◽  
Immunofluorescent Staining ◽  
Metabolic Enzyme ◽  
Vitamin A Metabolism ◽  
Expression And Activity

Abstract Background Mutation in a tuberous sclerosis gene (TSC1 or 2) leads to continuous activation of the mammalian target of rapamycin (mTOR). mTOR activation alters various cellular functions including cellular metabolism. In association with altered metabolism, several studies have shown reduced retinoic acid receptor beta (RARβ) expression. Investigation of the altered metabolic process can offer the identification of novel therapeutic targets and therapeutic strategies in diseases caused by TSC mutation with limited treatment options. Methods RARβ expression, metabolic enzymes expression and activity were assessed in human kidney angiomyolipoma cell line, primary lymphangioleiomyomatosis (LAM) tissue derived LAM cell lines as well as primary LAM lung tissue sections. TaqMan arrays, enzyme activities, qRT-PCRs, immunohistochemistry, immunofluorescent staining, Western blotting and metabolic enzyme regulating miRNAs were analysed. The functional effects of retinoic acid (RA) and rapamycin were tested in a scratch assay and in a 3D aggregate tissue system to assess the ability of cell migration. Results Metabolic enzyme arrays revealed a general deregulation of many enzymes involved in vitamin A metabolism including aldehyde dehydrogenases (ALDHs), alcohol dehydrogenases (ADHs) and Cytochrome P450 2E1 (CYP2E1). Furthermore, RARβ downregulation was a characteristic feature of all TSC-deficient cells and tissues. Combination of the two FDA approved drugs -RA for acute myeloid leukaemia and rapamycin for TSC mutation- normalised metabolic enzyme activity, restored RARβ expression and reduced cellular migration. Conclusion Deregulation of vitamin A metabolizing enzymes is a feature of TSC mutation. RA can normalize RARβ levels and limit migration. Combination of RA with reduced dose of rapamycin might be able to decrease adverse effects of rapamycin offering an alternative treatment for patients with TSC mutation.

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