Identification of genetic polymorphisms associated with interindividual variability of vitamin A concentration in adipose tissue of healthy male adults.

BACKGROUND: Adipose tissue vitamin A (VA), i.e. mainly retinol (RET) and its esters, comes from preformed VA and proVA carotenoids present in our food. Adipose tissue VA acts as hormonal cue maintaining essential aspects of adipocyte biology which includes fat mobilization and catabolism, energy balance and glucose homeostasis, and it is thus of particular interest to study its determinants, including genetic ones. Hence, this study aimed to identify genetic variations associated with adipose tissue VA concentration. METHODS: Forty-two healthy male adults received, in a randomized crossover design, 3 test meals. Periumbilical adipose tissue samples were collected on 6 occasions, i.e. at fast and 8h after consumption of each meal. RET concentration was measured in both plasma and the adipose tissue following saponification. Participants were genotyped using whole-genome microarrays. A total of 1305 SNPs in or near 27 candidate genes were included for univariate analysis. Partial least squares regression (PLS) was carried out to find the best combination of SNPs associated with the interindividual variability in adipose tissue RET concentration. RESULTS: Adipose tissue RET concentration was not associated with plasma RET concentrations (r=-0.184, p=0.28). Interindividual variability of adipose tissue RET concentration was high (CV=62%). Twenty-nine SNPs were significantly (p<0.05) associated with adipose tissue RET concentration and a PLS regression model identified 16 SNPs as explanatory variables of this concentration. The SNPs were in or near PPARG, RXRA, STRA6, CD36, FFAR4, ALDH1A1, MGLL, DGAT2, and PKD1L2. CONCLUSION: A combination of 16 SNPs has been associated with the interindividual of adipose tissue VA concentration in humans. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov registration number NCT02100774.

Characterization of the interindividual variability of lutein and zeaxanthin concentrations in the adipose tissue of healthy male adults and identification of combinations of genetic variants associated with it.

Lutein (L) and zeaxanthin (Z) are involved in visual function and could prevent age-related macular degeneration and chronic diseases and improve cognitive performances. Adipose tissue is the main storage site for these xanthophylls (Xanth). The factors affecting their concentrations in this tissue remain poorly understood but in animal models, genetic variations in apolipoprotein E and ß-carotene oxygenase 2 have been associated with adipose tissue L concentration. Therefore, the aims of this study were to better characterize the interindividual variability of adipose tissue Xanth concentration and to identify single nucleotide polymorphisms (SNPs) associated with it. Periumbilical subcutaneous adipose tissue samples were collected on 6 occasions in 42 healthy adult males and L and Z concentrations were measured by HPLC. Participants had their whole genome genotyped and the associations of 3589 SNPs in 49 candidate genes with the concentrations of L and Z were measured. Mean L and Z concentrations were 281 ± 27 and 150 ± 14 nmol g-1 proteins, respectively. There was no significant correlation between plasma and adipose tissue Xanth concentrations, although the correlation for L approached significance (Pearson's r = 0.276, p = 0.077). Following univariate filtering, 109 and 97 SNPs were then entered into a partial least squares regression analysis to identify the combination of SNPs that explained best adipose tissue concentration of L and Z, respectively. A combination of 7 SNPs in ELOVL5, PPARG, ISX and ABCA1, explained 58% of the variability in adipose tissue L concentration while 11 SNPs located in or near PPARG, ABCA1, ELOVL5, CXCL8, IRS1, ISX, MC4R explained 53% of the variance in adipose tissue Z concentration. This suggests that some genetic variations influence the concentrations of these Xanth in adipose tissue and could therefore indirectly influence the health effects of these compounds. Clinical Trial Registry: https://ClinicalTrials.gov registration number NCT02100774.

Genetic Factors Contributing to Interindividual Variability of α-Tocopherol Levels in Subcutaneous Adipose Tissue among Healthy Adult Males.

In humans, α-tocopherol (α-TOC) is mainly stored in adipose tissue, where it participates in preventing damages induced by inflammation and reactive oxygen species. Factors, including genetic ones, that explain adipose tissue α-TOC concentration remain poorly understood. This study, therefore, aimed to characterize the interindividual variability of adipose tissue α-TOC concentration in healthy individuals and to identify single nucleotide polymorphisms (SNPs) associated with it. The study used a randomized cross-over design with 42 healthy adult males. α-TOC concentration was measured in fasting plasma and periumbilical adipose tissue samples, both at fast and 8 h after consumption of three standard meals. Partial least squares (PLS) regression was performed to identify SNPs associated with the interindividual variability of adipose tissue α-TOC concentration. Adipose tissue α-TOC concentration was not associated with fasting plasma concentration (Pearson's r = 0.24, 95% CI: [-0.08, 0.51]). There was a high interindividual variability of adipose tissue α-TOC concentration (CV = 61%). A PLS regression model comprising 10 SNPs in five genes (PPARG, ABCA1, BUD13, CD36, and MGLL) explained 60% (adjusted R2) of the variability of this concentration. The interindividual variability of adipose tissue α-TOC concentration in humans is due, at least partly, to SNPs in genes involved in α-TOC and triglyceride metabolism.

Tomato genotype but not crop water deficit matters for tomato health benefits in diet-induced obesity of C57BL/6JRj male mice.

Several studies have linked the intake of lycopene and/or tomato products with improved metabolic health under obesogenic regime. The aim was to evaluate the differential impact of supplementations with several tomato genotypes differing in carotenoid content and subjected to different irrigation levels on obesity-associated disorders in mice. In this study, 80 male C57BL/6JRj mice were assigned into 8 groups to receive: control diet, high fat diet, high fat diet supplemented at 5 % w/w with 4 tomato powders originating from different tomato genotypes cultivated under control irrigation: H1311, M82, IL6-2, IL12-4. Among the 4 genotypes, 2 were also cultivated under deficit irrigation, reducing the irrigation water supply by 50 % from anthesis to fruit harvest. In controlled irrigation treatment, all genotypes significantly improved fasting glycemia and three of them significantly lowered liver lipids content after 12 weeks of supplementation. In addition, IL6-2 genotype, rich in ß-carotene, significantly limited animal adiposity, body weight gain and improved glucose homeostasis as highlighted in glucose and insulin tolerance tests. No consistent beneficial or detrimental impact of deficit irrigation to tomato promoting health benefits was found. These findings imply that the choice of tomato genotype can significantly alter the composition of fruit carotenoids and phytochemicals, thereby influencing the anti-obesogenic effects of the fruit. In contrast, deficit irrigation appears to have an overall insignificant impact on enhancing the health benefits of tomato powder in this context, particularly when compared to the genotype-related variations in carotenoid content.

Effect of long-term deficit irrigation on tomato and goji berry quality: from fruit composition to in vitro bioaccessibility of carotenoids.

Drought is a persistent challenge for horticulture, affecting various aspects of fruit development and ultimately fruit quality, but the effect on nutritional value has been under-investigated. Here, fruit quality was studied on six tomato genotypes and one goji cultivar under deficit irrigation (DI), from fruit composition to in vitro bioaccessibility of carotenoids. For both species, DI concentrated most health-related metabolites in fresh fruit. On a dry mass basis, DI increased total phenolic and sugar concentration, but had a negative or insignificant impact on fruit ascorbic acid, organic acid, and alcohol-insoluble matter contents. DI also reduced total carotenoids content in tomato (-18.7% on average), especially ß-carotene (-32%), but not in goji berry DW (+15.5% and +19.6%, respectively). DI reduced the overall in vitro bioaccessibility of carotenoids to varying degrees depending on the compound and plant species. Consequently, mixed micelles produced by digestion of fruits subjected to DI contained either the same or lesser quantities of carotenoids, even though fresh fruits could contain similar or higher quantities. Thus, DI effects on fruit composition were species and genotype dependent, but an increase in the metabolite concentration did not necessarily translate into greater bioaccessibility potentially due to interactions with the fruit matrix.

Effect of tomato, tomato-derived products and lycopene on metabolic inflammation: from epidemiological data to molecular mechanisms.

The goal of this narrative review is to summarise the current knowledge and limitations related to the anti-inflammatory effects of tomato, tomato-derived products and lycopene in the context of metabolic inflammation associated to cardiometabolic diseases. The potential of tomato and tomato-derived product supplementation is supported by animal and in vitro studies. In addition, intervention studies provide arguments in favour of a limitation of metabolic inflammation. This is also the case for observational studies depicting inverse association between plasma lycopene levels and inflammation. Nevertheless, current data of intervention studies are mixed concerning the anti-inflammatory effect of tomato and tomato-derived products and are not in favour of an anti-inflammatory effect of pure lycopene in humans. From epidemiological to mechanistic studies, this review aims to identify limitations of the current knowledge and gaps that remain to be filled to improve our comprehension in contrasted anti-inflammatory effects of tomato, tomato-derived products and pure lycopene.

Bioaccumulated provitamin A in black soldier fly larvae is bioavailable and capable of improving vitamin A status of gerbils.

The aim was to study whether provitamin A (proVA), which can bioaccumulate in black soldier fly larvae (BSFL), is bioavailable and can restore VA status in mammals. A model for studying the metabolism of this vitamin, the gerbil, was either fed a standard diet (C+ group), a diet without VA (C-), a diet in which VA was provided by ß-carotene (ß-C) from sweet potatoes (SP), or a diet in which VA was provided by ß-C from BSFL that had been fed sweet potatoes (BSFL). The animals were killed at the end of the supplementation period and ß-C, retinol and retinyl esters were measured in plasma and liver. As expected ß-C was not detected in plasma and liver of the C+ and C- groups. ß-C concentrations were lower (p < 0.05) in plasma and liver of the BSFL group as compared to the SP group. Liver retinol and retinyl ester concentrations were lower in the C- group than in all the other groups (p < 0.05). These concentrations were not significantly different in the C+ and SP groups while they were lower in the BSFL group (p < 0.05 for retinyl oleate and retinyl linoleate). In total, the liver stock of retinol equivalent was almost twice lower in the BSFL group than in the SP group. Thus, ß-C present in the BSFL matrix is bioavailable and capable of improving VA status, but this matrix decreases its effectiveness by a factor of around two compared to the sweet potato matrix.

The Incorporation of Curcuminoids in Gamma-Cyclodextrins Improves Their Poor Bioaccessibility, Which Is due to Both Their Very Low Incorporation into Mixed Micelles and Their Partial Adsorption on Food.

SCOPE: Turmeric curcuminoids mainly consist of curcumin (CUR), demethoxycurcumin (dCUR), and bisdemethoxycurcumin (bdCUR). CUR displays low bioavailability, partly due to poor solubilization in the intestinal lumen during digestion, while data for dCUR and bdCUR are scarce. The study aims to investigate the bioaccessibility of curcuminoids from turmeric extracts or from gamma-cyclodextrins, considering potential interactions with food. METHODS AND RESULTS: Using an in vitro digestion model (correlation with CUR bioavailability: r = 0.99), the study shows that curcuminoid bioaccessibility from turmeric extract without food is low: bdCUR (11.5 ± 0.6%) > dCUR (1.8 ± 0.1%) > CUR (0.8 ± 0.1%). Curcuminoids incorporated into gamma-cyclodextrins display higher bioaccessibilities (bdCUR: 21.1 ± 1.6%; dCUR: 14.3 ± 0.9%; CUR: 11.9 ± 0.7%). Curcuminoid bioaccessibility is highest without food (turmeric extract: 2.0 ± 0.1%; gamma-cyclodextrins: 12.4 ± 0.8%) and decreases with a meat- and potato-based meal (turmeric extract: 1.1 ± 0.2%; gamma-cyclodextrins: 2.4 ± 0.3%) or a wheat-based meal (turmeric extract: 0.1 ± 0.0%; gamma-cyclodextrins: 0.3 ± 0.1%). Curcuminoids exhibit low (<10%) incorporation efficiencies into synthetic mixed micelles (bdCUR > dCUR > CUR). CONCLUSIONS: bdCUR and dCUR show greater bioaccessibilities versus CUR. Food diminishes curcuminoid bioaccessibility, likely by adsorption mechanisms. Gamma-cyclodextrins improve curcuminoid bioaccessibility.

The zeaxanthin present in a tomato line rich in this carotenoid is as bioavailable as that present in the food sources richest in this xanthophyll.

It is strongly suspected that, like lutein, zeaxanthin (ZEA) plays a biological role in the human eye. Many studies also suggest that it could reduce the risk of age-related macular degeneration and improve cognition. Unfortunately, it is only present in a very limited number of foods. This is why a new tomato line, named "Xantomato", whose fruits can synthesize this compound, was generated. However, whether ZEA in Xantomato is bioavailable enough for Xantomato to qualify as a nutritionally relevant ZEA source is not known. The objective was to compare the bioaccessibility and intestinal cell uptake efficiency of ZEA from Xantomato to that present in the richest sources of this compound. Bioaccessibility was assessed using in vitro digestions and uptake efficiency using Caco-2 cells. Xantomato ZEA bioaccessibility was not statistically different from that of common fruits and vegetables rich in this compound. Xantomato ZEA uptake efficiency (7.8%) was lower (P < 0.05) than that of orange pepper (10.6%) but not different from that of corn (6.9%). Therefore, the results of the in vitro digestion/Caco-2 cell model suggest that Xantomato ZEA could be as bioavailable as that found in common food sources of this compound.

Fat-soluble vitamin and phytochemical metabolites: Production, gastrointestinal absorption, and health effects.

Consumption of diets rich in fruits and vegetables, which provide some fat-soluble vitamins and many phytochemicals, is associated with a lower risk of developing certain degenerative diseases. It is well accepted that not only the parent compounds, but also their derivatives formed upon enzymatic or nonenzymatic transformations, can produce protective biological effects. These derivatives can be formed during food storage, processing, or cooking. They can also be formed in the lumen of the upper digestive tract during digestion, or via metabolism by microbiota in the colon. This review compiles the known metabolites of fat-soluble vitamins and fat-soluble phytochemicals (FSV and FSP) that have been identified in food and in the human digestive tract, or could potentially be present based on the known reactivity of the parent compounds in normal or pathological conditions, or following surgical interventions of the digestive tract or consumption of xenobiotics known to impair lipid absorption. It also covers the very limited data available on the bioavailability (absorption, intestinal mucosa metabolism) and summarizes their effects on health. Notably, despite great interest in identifying bioactive derivatives of FSV and FSP, studying their absorption, and probing their putative health effects, much research remains to be conducted to understand and capitalize on the potential of these molecules to preserve health.

The Interindividual Variability of Phytofluene Bioavailability is Associated with a Combination of Single Nucleotide Polymorphisms.

SCOPE: Phytofluene is a colorless carotenoid with potential health benefits that displays a higher bioavailability compared to carotenoids such as lutein, ß-carotene or lycopene. Several studies suggest its bioavailability displays an elevated interindividual variability. The aim of this work is to investigate whether a combination of SNPs is associated with this variability. METHODS AND RESULTS: Thirty-seven healthy adult males consume a test meal that provides phytofluene from a tomato puree. Phytofluene concentrations are measured at fast and in chylomicrons at regular time intervals after meal intake. Identification of the combination of SNPs that best explained the interindividual variability of the phytofluene response is assessed by partial least squares regression. There is a large interindividual variability in the phytofluene response, with CV = 88%. Phytofluene bioavailability is positively correlated with fasting plasma phytofluene concentration (r = 0.57; p = 2 × 10-4 ). A robust partial least squares regression model comprising 14 SNPs near or within 11 genes (ABCA1-rs2487059, rs2515629, and rs4149316, APOC1-rs445925, CD36-rs3211881, ELOVL5-rs6941533, FABP1-rs10185660, FADS3-rs1000778, ISX-rs130461, and rs17748559, LIPC-rs17240713, LPL-rs7005359, LYPLAL1-rs1351472, SETD7-rs11936429) explains 51% (adjusted R2 ) of the interindividual variability in phytofluene bioavailability. CONCLUSIONS: This study reports a combination of SNPs that is associated with a significant part of the interindividual variability of phytofluene bioavailability in a healthy male adult population.

Vitamin A deficiency during the perinatal period induces changes in vitamin A metabolism in the offspring. The regulation of intestinal vitamin A metabolism via ISX occurs only in male rats severely vitamin A-deficient.

PURPOSE: 1) To test the hypothesis of the existence of a perinatal vitamin A (VA) programming of VA metabolism and to better understand the intestinal regulation of VA metabolism. METHODS: Offspring from rats reared on a control (C) or a VA-deficient (D) diet from 6 weeks before mating until offspring weaning, i.e., 7 weeks after mating, were themselves reared on a C or D diet for 19 weeks, resulting in the following groups: C-C (parents fed C-offspring fed C), D-C, C-D and D-D. VA concentrations were measured in plasma and liver. ß-Carotene bioavailability and its intestinal conversion rate to VA, as well as vitamin D and E bioavailability, were assessed after gavages with these vitamins. Expression of genes involved in VA metabolism and transport was measured in intestine and liver. RESULTS: C-D and D-D had no detectable retinyl esters in their liver. Retinolemia, hepatic retinol concentrations and postprandial plasma retinol response to ß-carotene gavage were higher in D-C than in C-C. Intestinal expression of Isx was abolished in C-D and D-D and this was concomitant with a higher expression of Bco1, Scarb1, Cd36 and Lrat in males receiving a D diet as compared to those receiving a C diet. ß-Carotene, vitamin D and E bio-availabilities were lower in offspring receiving a D diet as compared to those receiving a C diet. CONCLUSION: A VA-deficient diet during the perinatal period modifies the metabolism of this vitamin in the offspring. Isx-mediated regulation of Bco1 and Scarb1 expression exists only in males severely deficient in this vitamin. Severe VA deficiency impairs ß-carotene and vitamin D and E bioavailability.

Post-Harvest Atmospheric Pressure and Composition Modify the Concentration and Bioaccessibility of α- and ß-Carotene in Carrots and Sweet Potatoes.

Provitamin A (proVA) carotenoid synthesis and degradation are strongly influenced by environmental factors, including during post-harvest storage. Hypobaric and hyperbaric storages increase the shelf-life of many crops, but their effects on proVA carotenoids are not known. Our aim was to investigate the effects of modifications of atmospheric pressure and composition on α- and ß-carotene concentration and bioaccessibility during the post-harvest storage of carrots and sweet potatoes. Vegetables were stored for 11-14 days at 20 °C in the dark in chambers with modified pressure and O2 concentrations. In carrots, α- and ß-carotene concentrations increased significantly during storage, but compared to the control, they were significantly lower in hyperbaria (-23 and -26%, respectively), whereas they did not differ significantly in hypoxia and hypobaria. In sweet potatoes, α- and ß-carotene concentrations decreased significantly during storage, but neither hypoxia, hypobaria nor hyperbaria led to any significant change compared to the control. There was a significant increase for carrot α- and ß-carotene bioaccessibility in hypobaria and hyperbaria, while there was a significant decrease for sweet potato ß-carotene bioaccessibility in hypobaria/hypoxia and normobaria/hypoxia (-45% and -65% vs. control, respectively). Atmospheric pressure and composition during the post-harvest storage of carrots and sweet potatoes modified the concentration and bioaccessibility of proVA carotenoids.

ß-Carotene Bioavailability and Conversion Efficiency Are Significantly Affected by Sex in Rats: First Observation Suggesting a Possible Hormetic Regulation of Vitamin A Metabolism in Female Rats.

SCOPE: To study the effect of variation in dietary vitamin A (VA) content on its hepatic and intestinal metabolism. METHODS AND RESULTS: Adult female and male rats are fed with diets containing 400, 2300, or 9858 IU kg-1 VA for 31-33 weeks. VA concentrations are measured in plasma and liver. Bioavailability and intestinal conversion efficiency of ß-carotene to VA are assessed by measuring postprandial plasma ß-carotene and retinyl palmitate concentrations after force-feeding rats with ß-carotene. Expression of genes involved in VA metabolism, together with concentrations of RBP4, BCO1, and SR-BI proteins, are measured in the intestine and liver of female rats. Plasma retinol concentrations are lower and hepatic free retinol concentrations are higher in females than in males. There is no effect of dietary VA content on ß-carotene bioavailability and its conversion efficiency, but bioavailability is higher and conversion efficiency is lower in females than in males. The expression of most genes exhibited a U-shaped dose response curve depending on VA intake. CONCLUSIONS: ß-Carotene bioavailability and conversion efficiency to VA are affected by the sex of rats. Results of gene expression suggest a hormetic regulation of VA metabolism in female rats.

Vitamin A Deficiency during the Perinatal Period and First Weeks of Life Modifies Vitamin A and Lipid Postprandial Metabolism in Both Female and Male Young Rats.

SCOPE: The effect of vitamin A deficiency on vitamin A and lipid postprandial metabolism in young rats is addressed, considering the effect of sex. METHODS AND RESULTS: Sprague-Dawley rats are fed either 400 UI.kg-1 vitamin A diet (vitamin A-deficient (VAD) diet) or 2300 UI.kg-1 vitamin A (control diet), before being mated. Mothers receive the same VAD or control diet during gestation and lactation. Offspring receive the same diet than mothers until 8 weeks of age. VAD diet-fed female and male offspring display a severe vitamin A deficiency with no body weight or glucose tolerance defects. Fasting plasma triglyceride concentrations are decreased in VAD diet-fed animals compared to controls (p < 0.05). Retinyl ester postprandial responses after vitamin A gavage, expressed as area under the curves, are not different in VAD diet-fed and control animals, although retinyl ester postprandial peak is significantly delayed (p < 0.05) in VAD diet-fed rats. Lipids also accumulate in the distal part of the intestine after gavage and [1-13 C]-oleate postprandial response is decreased in VAD diet-fed males. CONCLUSION: Vitamin A deficiency modulates both vitamin A absorption rate and lipid postprandial metabolism, which can partly explain the altered fasting lipid status observed in VAD diet-fed offspring.

Mechanistic aspects of carotenoid health benefits - where are we now?

Dietary intake and tissue levels of carotenoids have been associated with a reduced risk of several chronic diseases, including cardiovascular diseases, type 2 diabetes, obesity, brain-related diseases and some types of cancer. However, intervention trials with isolated carotenoid supplements have mostly failed to confirm the postulated health benefits. It has thereby been speculated that dosing, matrix and synergistic effects, as well as underlying health and the individual nutritional status plus genetic background do play a role. It appears that our knowledge on carotenoid-mediated health benefits may still be incomplete, as the underlying mechanisms of action are poorly understood in relation to human relevance. Antioxidant mechanisms - direct or via transcription factors such as NRF2 and NF-κB - and activation of nuclear hormone receptor pathways such as of RAR, RXR or also PPARs, via carotenoid metabolites, are the basic principles which we try to connect with carotenoid-transmitted health benefits as exemplified with described common diseases including obesity/diabetes and cancer. Depending on the targeted diseases, single or multiple mechanisms of actions may play a role. In this review and position paper, we try to highlight our present knowledge on carotenoid metabolism and mechanisms translatable into health benefits related to several chronic diseases.

Using black soldier fly larvae reared on fruits and vegetables waste as a sustainable dietary source of provitamin a carotenoids.

We showed that black soldier fly larvae reared on fruits and vegetables rich in provitamin A carotenoids can accumulate significant amounts of these vitamin A precursors. Using a simulated gastro-intestinal digestion model, we demonstrated that α- and ß-carotene from the larvae are as bioaccessible as from the fruits and vegetables they were reared on. We calculated that provitamin A carotenoid-rich larvae have the capacity to provide more vitamin A than fruits and vegetables rich in these molecules. Remarkably, the incorporation of usual quantities of these larvae in feed could cover the needs of several production animals for this vitamin. Thus, our findings suggest that rearing black soldier fly larvae on by-products or waste rich in provitamin A carotenoids could be a sustainable strategy to recycle a fraction of vitamin A back into the food chain and could represent a new approach to fight against vitamin A deficiency.

The influence of nutrigenetics on biomarkers of selenium nutritional status.

Selenium (Se) is an essential micronutrient for human biology that executes its functions as the amino acid selenocysteine via selenoproteins, which have important functions in, for example, antioxidation, immunomodulation, thyroid metabolism, and human fertility. Se nutritional status is assessed using the quantification of blood Se biomarkers, which are influenced by several factors, including diet, age, gender, smoking status, alcohol consumption, health condition, and the genetic characteristics of individuals. Nutrigenetic studies have identified single nucleotide polymorphisms in selenoproteins that might clarify the high variability in values reported for biomarkers of Se nutritional status in different populations, and the response of these biomarkers to Se supplementation with either organic or inorganic forms of Se. This review aims to (1) define the basic aspects of Se biology, (2) describe the current most commonly used biomarkers of Se nutritional status, and (3) provide a summary of associations between functional single nucleotide polymorphisms in selenoproteins and biomarkers of Se status in healthy populations.

From carotenoid intake to carotenoid blood and tissue concentrations - implications for dietary intake recommendations.

There is uncertainty regarding carotenoid intake recommendations, because positive and negative health effects have been found or are correlated with carotenoid intake and tissue levels (including blood, adipose tissue, and the macula), depending on the type of study (epidemiological vs intervention), the dose (physiological vs supraphysiological) and the matrix (foods vs supplements, isolated or used in combination). All these factors, combined with interindividual response variations (eg, depending on age, sex, disease state, genetic makeup), make the relationship between carotenoid intake and their blood/tissue concentrations often unclear and highly variable. Although blood total carotenoid concentrations <1000 nmol/L have been related to increased chronic disease risk, no dietary reference intakes (DRIs) exist. Although high total plasma/serum carotenoid concentrations of up to 7500 nmol/L are achievable after supplementation, a plateauing effect for higher doses and prolonged intake is apparent. In this review and position paper, the current knowledge on carotenoids in serum/plasma and tissues and their relationship to dietary intake and health status is summarized with the aim of proposing suggestions for a "normal," safe, and desirable range of concentrations that presumably are beneficial for health. Existing recommendations are likewise evaluated and practical dietary suggestions are included.