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The Journal of Nutrition Jan 2004Liver vitamin A (retinol) is obtained from several sources and is subject to multiple fates. Lecithin:retinol acyltransferase (LRAT), a microsomal enzyme present in... (Review)
Review
Liver vitamin A (retinol) is obtained from several sources and is subject to multiple fates. Lecithin:retinol acyltransferase (LRAT), a microsomal enzyme present in liver and several other retinol-metabolizing tissues, esterifies retinol that is associated with a cellular retinol-binding protein, CRBP or CRBP-II. Recent research has shown that LRAT mRNA expression and enzyme activity are regulated in a tissue-specific manner. In vitamin A-deficient liver, both LRAT mRNA and activity are significantly down-regulated as well as rapidly induced after the administration of vitamin A or its principal hormonal metabolite, retinoic acid (RA). In long-term feeding studies and the metabolic steady state, liver LRAT is expressed dose-dependently across a wide range of dietary vitamin A. Additionally, an RA-inducible cytochrome P450, P450RAI or CYP26, is down-regulated in liver during vitamin A deficiency and up-regulated dose-dependently by dietary vitamin A and exogenous RA. Based on these results, we propose that LRAT and CYP26 serve as two molecular mechanisms, coordinately regulated by all-trans-RA, to control the availability of retinol and RA, respectively. The LRAT reaction, besides providing a readily retrievable storage form of vitamin A, may regulate the availability of retinol to other pathways, while the CYP26 reaction may serve to prevent a detrimental "overshoot" of RA concentration. Moreover, retinoid metabolism in the liver is likely to be closely integrated with that in peripheral tissues through the rapid interorgan transfer and recycling of retinoids, affecting the whole-body economy of vitamin A.
Topics: Acyltransferases; Animals; Cloning, Molecular; Cytochrome P-450 Enzyme System; DNA, Complementary; Esterification; Gene Expression Regulation; Homeostasis; Liver; Nutritional Status; Retinoic Acid 4-Hydroxylase; Vitamin A
PubMed: 14704332
DOI: 10.1093/jn/134.1.269S -
Cellular and Molecular Life Sciences :... Jul 2003Beyond their classical nutritional roles, nutrients modify gene expression and function in target cells and, by so doing, affect many fundamental biological processes.... (Review)
Review
Beyond their classical nutritional roles, nutrients modify gene expression and function in target cells and, by so doing, affect many fundamental biological processes. An emerging example, which is the focus of this review, is the involvement of vitamin A in the regulation of the level and functioning of body fat reserves. Retinoic acid, the carboxylic acid form of vitamin A, is a transcriptional activator of the genes encoding uncoupling proteins, and results in animals indicate that whole body thermogenic capacity is related to the vitamin A status. Retinoic acid also influences adipocyte differentiation and survival, with high doses inhibiting and low doses promoting adipogenesis of preadipose cells in culture. Moreover, vitamin A status can influence the development and function of adipose tissues in whole animals, with a low vitamin A status favouring increased fat deposition.
Topics: Adipocytes; Adipose Tissue; Animals; Body Temperature Regulation; Homeostasis; Humans; Models, Biological; Receptors, Retinoic Acid; Vitamin A
PubMed: 12943220
DOI: 10.1007/s00018-003-2290-x -
British Journal of Cancer Feb 2023Increases in IL-6 by cancer-associated fibroblasts (CAFs) contribute to colon cancer progression, but the mechanisms involved in the increase of this tumor-promoting...
BACKGROUND
Increases in IL-6 by cancer-associated fibroblasts (CAFs) contribute to colon cancer progression, but the mechanisms involved in the increase of this tumor-promoting cytokine are unknown. The aim of this study was to identify novel targets involved in the dysregulation of IL-6 expression by CAFs in colon cancer.
METHODS
Colonic normal (N), hyperplastic, tubular adenoma, adenocarcinoma tissues, and tissue-derived myo-/fibroblasts (MFs) were used in these studies.
RESULTS
Transcriptomic analysis demonstrated a striking decrease in alcohol dehydrogenase 1B (ADH1B) expression, a gene potentially involved in IL-6 dysregulation in CAFs. ADH1B expression was downregulated in approximately 50% of studied tubular adenomas and all T1-4 colon tumors, but not in hyperplastic polyps. ADH1B metabolizes alcohols, including retinol (RO), and is involved in the generation of all-trans retinoic acid (atRA). LPS-induced IL-6 production was inhibited by either RO or its byproduct atRA in N-MFs, but only atRA was effective in CAFs. Silencing ADH1B in N-MFs significantly upregulated LPS-induced IL-6 similar to those observed in CAFs and lead to the loss of RO inhibitory effect on inducible IL-6 expression.
CONCLUSION
Our data identify ADH1B as a novel potential mesenchymal tumor suppressor, which plays a critical role in ADH1B/retinoid-mediated regulation of tumor-promoting IL-6.
Topics: Humans; Alcohol Dehydrogenase; Cancer-Associated Fibroblasts; Colonic Neoplasms; Fibroblasts; Interleukin-6; Lipopolysaccharides; Tretinoin; Vitamin A
PubMed: 36482184
DOI: 10.1038/s41416-022-02066-0 -
The Journal of Investigative Dermatology Feb 1999Retinol and retinyl esters are converted with time to slowly increasing amounts of all-trans retinoic acid (RA) in cultured human keratinocytes. Exogenous RA has been...
Retinol and retinyl esters are converted with time to slowly increasing amounts of all-trans retinoic acid (RA) in cultured human keratinocytes. Exogenous RA has been shown to limit retinol oxidation and to increase retinol esterification. Because significant amounts of retinol are present in biologic systems, we examined whether RA and all-trans-retinoyl-beta-D-glucuronide (RAG) interact with retinol in exhibiting their activities on HaCaT keratinocytes maintained in a retinoid-free culture system. RA was more potent than RAG and retinol in inducing ultrastructural changes attributed to retinoids, inhibiting cell proliferation as well as enhancing keratin 19 expression. In addition, retinoids were able to induce cellular retinoic acid-binding protein II mRNA levels in the cultures, whereas early RA and late RAG activity was detected. The described biologic effects of RA and RAG were diminished by simultaneous cell exposure to retinol. HaCaT cells quickly metabolized retinol to retinyl esters and consequently to low amounts of RA. RA treatment led to an early high peak of cellular RA followed by reduction to trace amounts. Treatment with RAG resulted in constantly high cellular RAG and low RA levels. Under the combined RA and retinol treatment retinyl esters were increased and RA was reduced in HaCaT cells, whereas extracellular RA levels were similar to those obtained by RA alone. On the other hand, the combination of RAG and retinol resulted in higher extracellular RAG, similar cellular RAG, and lower cellular RA levels than those obtained by RAG alone without any change in retinyl esters. This study demonstrates that retinoid signaling by RA and RAG is attenuated by simultaneous exposure of HaCaT keratinocytes in vitro to retinol. The presence of retinol in the medium alters the rate of RA or RAG metabolism and thus cellular RA concentrations. The intensity of retinoid signal is probably dependent on cellular RA levels. The resulting "antagonism" among retinoids is consistent with the presence of an auto-regulatory mechanism in human keratinocytes offering protection against excessive accumulation of cellular RA.
Topics: Blotting, Northern; Cell Division; Cell Line; Culture Media; Drug Interactions; Electrophoresis, Polyacrylamide Gel; Humans; Keratinocytes; Keratins; RNA, Messenger; Receptors, Retinoic Acid; Retinoids; Sodium Dodecyl Sulfate; Tretinoin; Vitamin A
PubMed: 9989790
DOI: 10.1046/j.1523-1747.1999.00496.x -
American Journal of Physiology.... Aug 2006Retinoids, including all-trans-retinoic acid (RA), are considered to have anti-inflammatory properties and are used therapeutically for diseases of the skin and certain...
Retinoids, including all-trans-retinoic acid (RA), are considered to have anti-inflammatory properties and are used therapeutically for diseases of the skin and certain cancers. However, few studies have addressed the effects of disease states on RA metabolism. The present study was conducted to better understand the effects of exogenous RA, both in the absence and presence of inflammation, on the distribution and metabolism of a dose of [3H]RA. Female Sprague-Dawley rats fed a low vitamin A diet were pretreated with RA (po), a low dose of lipopolysaccharide (LPS, ip), or their combination. Twelve hours later, albumin-bound [3H]RA was injected intravenously, and tissue organic- and aqueous-phase 3H was determined after 10 and 30 min. In liver and plasma, 3H-labeled organic metabolites (e.g., 4-oxo- and 4-hydroxy-RA) were isolated by solid-phase extraction. LPS-induced inflammation significantly reduced plasma retinol by 47%, increased total 3H in plasma at 10 min, and reduced total 3H in liver at both times. In contrast, RA pretreatment did not affect plasma retinol, significantly increased total 3H in plasma at both times, and did not affect liver total 3H. However, by 30 min, RA significantly increased [3H]RA metabolism in plasma, liver, lung, and small intestine, as indicated by greater 3H-labeled aqueous-phase and 3H-labeled organic-phase metabolites. The results presented here demonstrate that, although LPS-induced inflammation affects the organ distribution of RA, the ability of RA to induce its own catabolism is maintained during inflammation. Thus we conclude that RA and LPS act independently to alter RA metabolism in vitamin A-marginal rats.
Topics: Animals; Drug Combinations; Female; Homeostasis; Inflammation; Lipopolysaccharides; Metabolic Clearance Rate; Organ Specificity; Rats; Rats, Sprague-Dawley; Tissue Distribution; Tretinoin; Vitamin A; Vitamin A Deficiency
PubMed: 16825659
DOI: 10.1152/ajpgi.00011.2006 -
Biomedical Papers of the Medical... Jun 2024Retinoids participate in multiple key processes in the human body e.g., vision, cell differentiation and embryonic development. There is growing evidence of the...
AIMS
Retinoids participate in multiple key processes in the human body e.g., vision, cell differentiation and embryonic development. There is growing evidence of the relationship between retinol, its active metabolite- all-trans retinoic acid (ATRA) - and several pancreatic disorders. Although low levels of ATRA in pancreatic ductal adenocarcinoma (PDAC) tissue have been reported, data on serum levels of ATRA in PDAC is still limited. The aim of our work was to determine serum concentrations of retinol and ATRA in patients with PDAC, type-2 diabetes mellitus (T2DM), chronic pancreatitis (CHP) and healthy controls.
METHODS
High performance liquid chromatography with UV detection (HPLC) was used to measure serum levels of retinol and ATRA in 246 patients with different stages of PDAC, T2DM, CHP and healthy controls.
RESULTS
We found a significant decrease in the retinol concentration in PDAC (0.44 mg/L) compared to T2DM (0.65 mg/L, P<0.001), CHP (0.60 mg/L, P< 0.001) and healthy controls (0.61 mg/L, P<0.001), significant decrease of ATRA levels in PDAC (1.14 ug/L) compared to T2DM (1.37 ug/L, P<0.001) and healthy controls(1.43 ug/L, P<0.001). Differences between early stages (I+II) of PDAC and non-carcinoma groups were not significant. We describe correlations between retinol, prealbumin and transferrin, and correlation of ATRA and IGFBP-2.
CONCLUSION
Significant decrease in retinol and ATRA levels in PDAC compared to T2DM, healthy individuals and/or CHP supports existing evidence of the role of retinoids in PDAC. However, neither ATRA nor retinol are suitable for detection of early PDAC. Correlation of ATRA levels and IGFBP-2 provides new information about a possible IGF and retinol relationship.
Topics: Humans; Pancreatitis, Chronic; Vitamin A; Tretinoin; Diabetes Mellitus, Type 2; Male; Female; Middle Aged; Pancreatic Neoplasms; Aged; Carcinoma, Pancreatic Ductal; Adult; Case-Control Studies; Chromatography, High Pressure Liquid
PubMed: 38058194
DOI: 10.5507/bp.2023.049 -
The Journal of Investigative Dermatology Jul 1995We examined the regulation of cellular retinol-binding protein (CRBP) mRNA and protein expression in human skin in vivo by all-trans retinoic acid and all-trans retinol....
We examined the regulation of cellular retinol-binding protein (CRBP) mRNA and protein expression in human skin in vivo by all-trans retinoic acid and all-trans retinol. Treatment of human skin for 24 h with all-trans retinoic acid (0.1%) or all-trans retinol (1.6%) induced CRBP mRNA 5.5-fold (p < 0.01, n = 10) and 5.7-fold (p < 0.01, n = 5), respectively, compared with skin treated with vehicle or sodium lauryl sulfate (used as an irritant control). In vitro translation of poly A+ RNA from all-trans retinoic acid, all-trans retinol, sodium lauryl sulfate, and vehicle-treated human skin demonstrated that the observed increased CRBP mRNA in all-trans retinoic acid- and all-trans retinol-treated skin was able to direct increased (2.3-2.9-fold) CRBP protein synthesis. Riboprobe in situ hybridization revealed that CRBP mRNA was uniformly elevated throughout the epidermis and in dermal cells after all-trans retinoic acid treatment of human skin. Western analysis revealed that CRBP protein was elevated 3.2-fold (p < 0.01, n = 6) and 3.0-fold (p < 0.01, n = 6) after all-trans retinoic acid treatment of human skin in vivo for 24 and 96 h, respectively, compared with vehicle- and sodium lauryl sulfate-treated skin. In addition, functional CRBP levels measured by [3H]all-trans retinol binding were elevated 1.9-fold (p < 0.01, n = 6) and 3.5-fold (p < 0.01, n = 6) at 24 and 94 h, respectively, after all-trans retinoic acid treatment, compared with vehicle- or sodium lauryl sulfate-treated skin. Gel mobility shift analysis revealed that retinoid receptors in nuclear extracts from human skin formed a specific complex with a DNA probe containing the retinoic acid response element in the mouse CRBP gene. Monoclonal antibodies to nuclear retinoid receptors demonstrated that predominantly retinoic acid receptor-alpha/retinoid X receptor-alpha heterodimers bound to the CRBP retinoic acid response element. These data demonstrate that CRBP expression in human skin in vivo is regulated by exogenous all-trans retinoic acid and all-trans retinol.
Topics: Base Sequence; Humans; In Situ Hybridization; Molecular Sequence Data; RNA, Messenger; Receptors, Retinoic Acid; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Skin; Tretinoin; Vitamin A
PubMed: 7615982
DOI: 10.1111/1523-1747.ep12313352 -
The Journal of Biological Chemistry Apr 2000Retinol dehydrogenase (RDH), the enzyme that catalyzes the reduction of all-trans-retinal to all-trans-retinol within the photoreceptor outer segment, was the first...
Identification and characterization of all-trans-retinol dehydrogenase from photoreceptor outer segments, the visual cycle enzyme that reduces all-trans-retinal to all-trans-retinol.
Retinol dehydrogenase (RDH), the enzyme that catalyzes the reduction of all-trans-retinal to all-trans-retinol within the photoreceptor outer segment, was the first visual cycle enzymatic activity to be identified. Previous work has shown that this enzyme utilizes NADPH, shows a marked preference for all-trans-retinal over 11-cis-retinal, and is tightly associated with the outer segment membrane. This paper reports the identification of a novel member of the short chain dehydrogenase/reductase family, photoreceptor RDH (prRDH), using subtraction and normalization of retina cDNA, high throughput sequencing, and data base homology searches to detect retina-specific genes. Bovine and human prRDH are highly homologous and are most closely related to 17-beta-hydroxysteroid dehydrogenase 1. The enzymatic properties of recombinant bovine prRDH closely match those previously reported for RDH activity in crude bovine rod outer segment preparations. In situ hybridization and RNA blotting show that the PRRDH gene is expressed specifically in photoreceptor cells, and protein blotting and immunocytochemistry show that prRDH localizes exclusively to both rod and cone outer segments and that prRDH is tightly associated with outer segment membranes. Taken together, these data indicate that prRDH is the enzyme responsible for the reduction of all-trans-retinal to all-trans-retinol within the photoreceptor outer segment.
Topics: Alcohol Oxidoreductases; Amino Acid Sequence; Animals; Cattle; Cell Membrane; Humans; Molecular Sequence Data; NAD; Retinal Diseases; Retinaldehyde; Rod Cell Outer Segment; Vitamin A
PubMed: 10753906
DOI: 10.1074/jbc.275.15.11034 -
Canadian Medical Association Journal Apr 1980Experimental investigations of the antineoplastic effects of retinoids are reviewed in this paper. In vitro studies have shown that the hyperplastic and metaplastic... (Review)
Review
Experimental investigations of the antineoplastic effects of retinoids are reviewed in this paper. In vitro studies have shown that the hyperplastic and metaplastic response to chemical carcinogens of mouse prostate cultures is suppressed by the addition of retinoids to the culture medium, that retinoids can partially inhibit the morphologic transformation of 10T 1/2 cells by physical or chemical carcinogens, and that the growth of some non-neoplastic and some neoplastic cell lines can be inhibited by retinoids. In vivo studies have shown that retinoids can suppress papilloma and carcinoma development (the promotion phase) in the two-stage skin carcinogenesis assay, inhibit mammary and bladder carcinogenesis in mice and rats, and inhibit the growth of some transplantabletumor lines. So far it has not been possible to inhibit predictably tumour formation in the intestinal tract or the respiratory tract of rodents. Almost all the synthetic retinoids have a higher therapeutic index than the natural retinoids in the prevention or treatment of cancer.
Topics: Animals; Cell Transformation, Neoplastic; Lung Neoplasms; Neoplasms, Experimental; Skin Neoplasms; Tretinoin; Vitamin A
PubMed: 6988069
DOI: No ID Found -
Renal Failure Dec 2022Retinol concentrations in serum are significantly higher in patients on hemodialysis (HD) compared to healthy controls. Its lower concentrations have been reported to be...
BACKGROUND
Retinol concentrations in serum are significantly higher in patients on hemodialysis (HD) compared to healthy controls. Its lower concentrations have been reported to be an independent predictor of mortality. ATRA - all-trans retinoic acid - is an important compound related to retinol. The objective was to determine ATRA concentrations in serum and to find their association with the prognosis of patients on long-term HD.
METHODS
ATRA was determined by high-performance liquid chromatography in a group of 247 HD patients (follow-up five years) and 54 healthy controls.
RESULTS
Although serum retinol concentrations were higher in the studied cohort of HD patients, ATRA was lower - median 1.13 (interquartile range 0.90-1.60) ng/mL in HD patients versus 1.42 (1.08-1.63) ng/mL in healthy controls, = 0.02. Lower ATRA was significantly related to overall mortality of HD patients (HR (95%CI) 0.63 (0.47-0.85) per interquartile range, = 0.003). The best prognosis was observed in patients with concentrations of both ATRA and retinol above the median ( = 0.003).
CONCLUSIONS
We detected decreased retinoic acid levels in HD patients compared to healthy controls. Lower concentrations of ATRA represent a significant predictor of mortality and provide additional information to retinol.
Topics: Humans; Tretinoin; Vitamin A; Prognosis; Chromatography, High Pressure Liquid; Renal Dialysis
PubMed: 36330606
DOI: 10.1080/0886022X.2022.2126786