Retinoid metabolism and nuclear receptor responses: New insights into coordinated regulation of the PPAR–RXR complex

Department of Human Nutrition, Ohio State University, Columbus, OH 43210, USA.
FEBS Letters (Impact Factor: 3.17). 02/2008; 582(1):32-8. DOI: 10.1016/j.febslet.2007.11.081
Source: PubMed


Retinoids, naturally-occurring vitamin A derivatives, regulate metabolism by activating specific nuclear receptors, including the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). RXR, an obligate heterodimeric partner for other nuclear receptors, including peroxisome proliferator-activated receptors (PPARs), helps coordinate energy balance. Recently, many groups have identified new connections between retinoid metabolism and PPAR responses. We found that retinaldehyde (Rald), a molecule that can yield RA through the action of retinaldehyde dehydrogenases (Raldh), is present in fat in vivo and can inhibit PPAR gamma-induced adipogenesis. In vitro, Rald inhibits RXR and PPAR gamma activation. Raldh1-deficient mice have increased Rald levels in fat, higher metabolic rates and body temperatures, and are protected against diet-induced obesity and insulin resistance. Interestingly, one specific asymmetric beta-carotene cleavage product, apo-14'-carotenal, can also inhibit PPAR gamma and PPAR alpha responses. These data highlight how pathways of beta-carotene metabolism and specific retinoid metabolites may have direct distinct metabolic effects.

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Available from: Ouliana Ziouzenkova, Aug 14, 2014
    • "Vitamin A, or retinol, is essential for a variety of physiological processes, including vision, immune function, reproduction, and embryonic development including cellular growth and differentiation (Blomhoff and Blomhoff, 2006; Stephensen, 2001; Mora et al., 2008). Vitamin A is not biologically active per se, but within the tissue it is oxidized to retinaldehyde, and then to retinoic acid (Blomhoff and Blomhoff, 2006), and this regulates the transcription of a variety of target genes via the activation of specific nuclear receptors, including retinoic acid receptors and retinoid X receptors (Blomhoff and Blomhoff, 2006; Ziouzenkova and Plutzky, 2008; Shulman and Mangelsdorf, 2005). Vitamin A and b-carotene supplementation has been shown to reduce maternal mortality and morbidity in women (Gogia and Sachdev, 2010; Christian, 2002), and improve mammary health in dairy cows around dry-off and weaning (Tjoelker et al., 1990). "
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    ABSTRACT: Vitamin A plays important roles in many physiological processes including, vision, growth, development and reproduction. Recently, vitamin A was shown to have a thermogenic effect via induction of uncoupling protein 1 expression in brown adipose tissue. We investigated the effect of vitamin A supplementation on pregnant goats and the metabolites related to does’ health, and their kids’ viability and growth performance. Thirty pregnant does were assigned to two experimental groups of 15 animals each. The first group was injected with vitamin A (50000 IU) twice a week for one month before kidding. The second (control) group was injected with saline. Sera were obtained from the does and kids to evaluate health related metabolites. The kids’ birth and weaning weights, body weight gain, rectal temperature, and the incidence of stillbirth were recorded. Vitamin A supplementation increased serum levels of vitamin A and globulin of the does before and after kidding. In addition, it increased serum levels of glucose, triglycerides and cholesterol after kidding (P < 0.05). However, serum levels of AST and ALT before kidding were decreased (P < 0.05). Vitamin A supplementation to the pregnant doses increased their kids’ serum level of vitamin A, rectal temperature, birth weight and body weight gain (P < 0.05), while it decreased kid mortality rate. This study indicated that vitamin A supplementation to pregnant goats enhanced their health, and their kids’ viability and growth performance, thus improving profitability.
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    • "All participants received interferon beta-1a (Avonex®) as treatment. Exclusion criteria included evidence of any disease affecting the immune system balance, abnormality of liver enzyme function , malnutrition, an increase in EDSS score, clinically isolated syndrome (CIS), and neuromyelitis optica (Parés et al. 2008; Ziouzenkova and Plutzky 2008). Random permuted blocks within the strata (age and sex) were used for the study design. "
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    ABSTRACT: Multiple sclerosis (MS) is an autoinflammatory condition of the central nervous system with impaired T helper (Th)17 and regulatory T cell (Treg) balance that is involved in disease immunopathogenesis. The vitamin A active metabolite, retinoic acid, can re-establish this imbalance through the modulation of gene expression of specific nuclear receptors including Forkhead box P3 (FoxP3). At present, few data exist on the impact of vitamin A supplementation on T cell balance. This study reports the results of a clinical trial, over a 6-month period, of 36 relapsing-remitting MS (RRMS) patients that received vitamin A (25,000 IU retinyl palmitate) or placebo (one capsule of placebo per day). Peripheral blood mononuclear cells were isolated from patients, and the expression of FoxP3 and transforming growth factor (TGF)-β gene expression was measured using real-time PCR at the beginning and end of the study. The results of this study showed that vitamin A upregulated TGF-β and FoxP3 gene expression. Therefore, vitamin A supplementation can be considered as a new approach in MS prevention and treatment.
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    • "To summarize, the influence of beta-carotene on antioxidant enzyme activity is complex and difficult to interpret because beta-carotene could likely modify enzyme expression through hormone-like activity, phosphorylation processes and post-transcriptional modification of proteins (Ziouzenkova and Plutzky, 2008). The effects of beta-carotene supplementation in lead exposed males are comparable to those observed after NAC administration. "
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    ABSTRACT: The aim of this study was to determine whether beta-carotene administration reduces oxidative stress and influences antioxidant, mainly glutathione-related, defense systems in workers chronically exposed to lead. The population consisted of two randomly divided groups of healthy male volunteers exposed to lead. Workers in the first group (reference group) were not administered any antioxidants, while workers in the second group (CAR group) were treated orally with 10 mg of beta-carotene once a day for 12 weeks. Biochemical analysis included measuring markers of lead-exposure and oxidative stress in addition to the levels and activities of selected antioxidants. After treatment, levels of malondialdehyde, lipid hydroperoxides and lipofuscin significantly decreased compared with the reference group. However, the level of glutathione significantly increased compared with the baseline. Treatment with beta-carotene also resulted in significantly decreased glutathione peroxidase activity compared with the reference group, while the activities of other glutathione-related enzymes and of superoxide dismutase were not significantly changed. However, the activities of glucose-6-phosphate dehydrogenase and catalase, as well as the level of alpha-tocopherol, were significantly higher after treatment compared with the baseline. Despite controversy over the antioxidant properties of beta-carotene in vivo, our findings showed reduced oxidative stress after beta-carotene supplementation in chronic lead poisoning.
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