Retinyl Ester Response Research Articles

Validation of a Method for Estimating Vitamin A Absorption Efficiency Based on Compartmental Analysis of Post-Prandial Plasma Retinyl Ester Kinetics

Abstract Objectives Because good methods are not available to estimate vitamin A (VA) absorption, we evaluated an approach based on modeling retinyl ester response to an oral VA dose. Methods We generated data for 12 theoretical subjects, assigning values for VA absorption, stores, and kinetic parameters; we used WinSAAM (Simulation, Analysis and Modeling software) to simulate data (without and with 5% average error) for plasma chylomicron retinyl esters (RE) and retinol versus time (30 min to 8 h or 56 d, respectively) after ingestion of labeled VA; next we fit data to a previously-published 9-component model for VA metabolism to obtain “known” values for VA absorption. Then RE data only were modeled for each subject using a robust (n = 16 times) vs truncated sampling schedule (n = 10) and model-predicted absorptions were compared to known values. Areas under the plasma RE response curves (AUCs) were also calculated and compared to known absorption values. Results Known values for VA absorption based on modeling all data with error ranged from 54 – 92% (mean, 72%), VA stores from 160 – 1775 μmol, and chylomicron t1/2 from 6 – 12 min. Using the full sampling scheme for RE, the ratio of model-predicted to known absorption ranged from 0.927 – 1.06 (mean, 0.997); using the truncated scheme, the ratio was 0.814 – 1.13 (mean, 0.973). AUCs were not significantly correlated with known values for VA absorption (R2 = 0.112; P > 0.05), presumably because absorption and chylomicron catabolism are occurring simultaneously. Conclusions By modeling chylomicron RE tracer data after ingestion of labeled VA, absorption efficiency was estimated accurately using error-free data; using data with 5% error, estimates were within 10% of known values (full sampling) or within 20% (truncated). If subjects, after an overnight fast, consume a breakfast containing some fat and a known amount of VA, then no tracer is required to estimate VA absorption using this modeling approach. By incorporating a population-based design, the method could be used in children. Funding Sources Supported by Bill & Melinda Gates Foundation (Project Number OPP1115464) and HarvestPlus (BH183438).

Retinol and Retinyl Ester Responses in the Blood Plasma and Urine of Dogs after a Single Oral Dose of Vitamin A

Retinol and Retinyl Ester Responses in the Blood Plasma and Urine of Dogs after a Single Oral Dose of Vitamin A

Methodological Considerations in Determining Vitamin A and Carotenoid Bioactivity in Humans

At present there is little information regarding the quantitative vitamin A value of specific foods or meal patterns. Such information would aid in a more precise determination of the suitability of certain foods or diets to meet minimum and optimal nutritional needs for vitamin A. This knowledge deficit stems largely from the lack of well-developed models to assess the bioavailability of carotenoids, particularly provitamin A carotenoids, from foods. Literature values of carotenoid bioavailability (percent of ingested carotene absorbed) range from 1% to 99%, and variability is often high both within and between treatments. Current models generally fall into two categories: those employing outcomes that reflect efficacy, i.e., that rely on changes in one or more indicators of vitamin A status; and those which provide a more direct estimate of absorption and/or conversion efficiency of single doses of provitamin A carotenoids. the latter include oral–faecal balance models and post-prandial chylomicron retinyl ester response models. Absolute bioavailability, i.e., the mass of newly absorbed vitamin A derived from a given mass of provitamin A carotenoid consumed, is inherently more problematic to assess than relative bioavailability, in which two or more treatments are compared. One missing and key piece of information is the extent of post-absorptive conversion of provitamin A carotenoids to vitamin A in humans. Without such information, the contribution of absorbed β-carotene or plasma β-carotene to vitamin A status will remain clouded. Recent estimates of the vitamin A value of plant foods suggest that in some cases plant-based diets may be insufficient to improve vitamin A status, yet in some circumstances this prediction has proved inaccurate. This paper will contrast several of the more recent methods of assessing the bioavailability of food-borne provitamin A carotenoids to illustrate the potentially complementary nature of the two categories of bioavailability model.

Bioavailability of carotenoids in human subjects.

There is growing need for accurate information regarding the bioavailability of carotenoids, both with respect to carotenoids per se and to the vitamin A value of provitamin A carotenoids in foods or supplement preparations. Little quantitative information is currently available, owing primarily to the lack of adequate methods to assess carotenoid bioavailability. Methods applied to xenobiotic drugs are in most cases not useful for carotenoids, many of which circulate in appreciable quantities in human plasma. Reported ranges of carotenoid bioavailability (% dose absorbed) range from 1-99, and variability is generally high both within and between treatments. With the current methods, relative bioavailability is more readily assessed than absolute bioavailability. The most commonly applied methods include measuring the increase in plasma carotenoid concentration following chronic intervention, and use of postprandial chylomicron (PPC) carotenoid or retinyl ester response following a single dose of carotenoid. The advantages and limitations of these approaches, together with examples of each, are discussed. A new PPC approach utilizing extrinsic-stable-isotope-labelled vitamin A (2H4-labelled retinyl acetate) is under development in our laboratory, and examples of its application are presented. The currently available data suggest that oil solutions of carotenoids are more bioavailable than those from food matrices, and heating can improve the bioavailability of carotenoids from some food products. Increased availability of labelled carotenoids and retinoids should aid the development of reliable methods of carotenoid bioavailability assessment. Such data are needed for dietary recommendations, supplement formulation, and design of intervention strategies involving carotenoids.

Effect of simultaneous, single oral doses of β-carotene with lutein or lycopene on the β-carotene and retinyl ester responses in the triacylglycerol-rich lipoprotein fraction of men

The effects of lutein and lycopene on β-carotene absorption and cleavage were investigated in 12 male subjects. Responses of carotenoids and retinyl palmitate in the triacylglycerol-rich lipoprotein (TRL) fraction after a separate 15-mg β-carotene dose were compared with those after a dose of 15 mg β-carotene combined with 15 mg lycopene or lutein (given as natural concentrates or extracts). After combined dosing with lutein, the areas under the curve (AUCs) of β-carotene and retinyl palmitate in the TRL fraction, adjusted for the triacylglycerol response, were 66% (P = 0.019) and 74% (P < 0.059), respectively, compared with 100% after dosing with β-carotene alone. After combined dosing with lycopene these percentages were 90% and 101%, respectively (NS). β-carotene conversion, estimated from the ratio between the AUC for retinyl esters and β-carotene, assuming eccentric cleavage, was 69%, 71%, and 72% for treatment with only β-carotene, β-carotene combined with lycopene, and β-carotene combined with lutein, respectively. In addition, a pilot study was performed to evaluate application of TRL response curves to measure absorption of carotenoids from vegetable sources (15 mg carotenoid as carrots, spinach, and tomato paste). As compared with the carotenoid concentrates, responses were considerably lower or hardly measurable (β-carotene and retinyl palmitate after carrots, lutein after spinach), except for lycopene and retinyl palmitate after a single dose of tomato paste. In conclusion, this study showed that lutein, but not lycopene, negatively affected β-carotene absorption when given simultaneously with β-carotene but apparently had no effect on β-carotene cleavage. Am J Clin Nutr 1998;68:82–9.

Comparison of three fatty meals in healthy normolipidaemic men: high post‐prandial retinyl ester response to soybean oil

Oral fat tolerance tests (FTTs) have been widely used as a tool to investigate post-prandial lipaemia. However, there is no consensus regarding the type and amount of fat used in the tests. We compared three commonly used FTTs, each containing 63 g of fat: a mixed meal, a liquid cream meal and a liquid soybean oil meal. The study group consisted of 10 healthy normolipidaemic men. We measured triglycerides (TGs), retinyl esters (REs), apolipoprotein E (apoE), apolipoprotein B-48 (apoB-48) and apolipoprotein B-100 (apoB-100) in plasma and in triglyceride-rich lipoprotein (TRL) fractions separated by density-gradient ultracentrifugation at baseline and 3, 4, 6, and 8 h after the FTTs. We observed similar TGs, apoE, apoB-48 and apoB-100 responses after all three FTTs, despite the different fatty acid composition of the meals. In contrast, the commonly used marker for exogenous particles, RE, differed clearly when polyunsaturated (soybean oil) and saturated fat (cream or mixed meal) were used. The RE response in plasma (P < 0.005, repeated measures ANOVA), in chylomicrons (P < 0.013) and in very low-density lipoprotein (VLDL) 1 (P < 0.017), as well as the RE area under the incremental curve in plasma and chylomicron fractions, were markedly increased after the soybean oil meal compared with the mixed meal and cream meal tests. The peak of RE response occurred parallel to the responses of other markers (i.e. TG or apoB-48) of post-prandial TRL during soybean oil meal. In contrast, RE peak concentration was delayed after saturated fat-containing meals. After soybean oil, FTT plasma cholesterol concentration was lower and the chylomicron cholesterol concentration was higher compared with mixed or cream meals, but no differences were detected in post-prandial high-density lipoprotein (HDL)-cholesterol concentration. When the amount of fat is similar, post-prandial responses of TG, apoE, apoB-48, apoB-100 and HDL-cholesterol were comparable after different FTTs.

Studies on the bioconversion of β-carotene to active vitamin A in underprivileged Guatemalan children

The mechanism by which the rate of β-carotene conversion to active vitamin A in the enterocyte is poorly understood. It is postulated that body vitamin A status plays a very important role. Unitl recently, it has not been possible to detect and quantify the product of β-carotene bioconversion, i.e., retinal, in the gut, and retinyl ester, in the circulation. This study aimed at confirming that a rise in plasma retinyl palmitate concentration would occur after administration of β-carotene to underprivileged Guatemalan schoolchildren. Twenty rural children, aged 7 to 11 years, received 30 mg of pure, crystalline β-carotene in oral capsules in the fasting state. Thirteen peri-urban poor children participated as controls; each received capsules of cellulose. Standard meals with low vitamin A levels were served during the observation period. Plasma levels of β-carotene, retinol, and retinyl palmitate were determined by HPLC at baseline, 2 hr, and 24 hr after ingestion of capsules. Anthropometric and biochemical characteristics were similar in both groups at baseline. An average increase of 0.15 ± 0.05 μmol/L in retinyl esters was observed in the supplemented group at 2 hr, with a return to baseline levels at 24 hr; whereas in the control group no retinyl esters were detected at all at any time. A tendency of a greater retinyl ester response with a lower baseline circulating retinol level was observed. This is the first instance in which β-carotene bioconversion to retinyl palmitate has been quantified in children. We propose that the rise in retinyl esters after oral administration of β-carotene could be used to examine the factors that influence the rate of bioconversion of β-carotene to active vitamin A.

Intestinal beta-carotene absorption and cleavage in men: response of beta-carotene and retinyl esters in the triglyceride-rich lipoprotein fraction after a single oral dose of beta-carotene

Postprandial response curves of beta-carotene and retinyl esters in a triglyceride-rich lipoprotein (TRL) fraction were evaluated as a potential measure of beta-carotene uptake and cleavage. beta-Carotene, retinyl ester, and triglyceride concentrations in the TRL fraction (density < 1.006 kg/L) and plasma were measured in 10 men for 8 or 16 h after an oral dose of 15 mg beta-carotene. The beta-carotene response, unlike the triglyceride and retinyl ester response, can be evaluated in the TRL fraction but not in plasma. Intraindividual variations in the triglyceride-adjusted response of beta-carotene and retinyl palmitate in TRL fractions were 23% and 20% and interindividual variations were 42% and 36%, respectively. A low beta-carotene response was associated with a high ratio between retinyl palmitate and beta-carotene responses (r = -0.56, P = 0.013). In conclusion, the measurement of beta-carotene and retinyl esters in the TRL fraction after a dose of beta-carotene with a vitamin A-free meal may be an appropriate method to study beta-carotene uptake and cleavage.

Apolipoprotein B-48 and retinyl ester responses to meals of varying monounsaturated fatty acid contents

Apolipoprotein B-48 and retinyl ester responses to meals of varying monounsaturated fatty acid contents

Postprandial triglyceride and retinyl ester responses to oral fat: effects of fructose

It has been shown that addition of fructose to an oral fat load results in higher postprandial concentrations of triglyceride. The present study, performed in 11 healthy volunteers, was initiated to see whether the effect of fructose on fat-induced lipemia also involved changes in postprandial concentrations of triglyceride-rich lipoproteins of intestinal origin. Vitamin A was used to label intestinal lipoproteins, and the retinyl palmitate concentrations were determined in plasma and in the Sf > 400 and Sf 20-400 lipoprotein fractions (Sf denotes the Svedberg flotation index). Addition of fructose (50 g) to a standard (40-g oral) fat load resulted in higher postprandial concentrations of triglyceride and retinyl palmitate in plasma and the Sf > 400 lipoprotein fraction (P < 0.001, analysis of variance), and the higher the fasting plasma triglyceride concentration, the greater the magnitude of the fructose effect (r = 0.83, P < 0.002). These data show that triglyceride-rich lipoproteins of intestinal origin play a role in the fructose-induced accentuation of postprandial lipemia.

Sex differences in postabsorptive plasma vitamin A transport

This study examined postabsorptive plasma vitamin A after doses of retinyl palmitate in healthy men (n = 28) and women (n = 31). On consecutive days one physiologic [3000 retinol equivalents (RE)] and one pharmacologic dose (105,000 RE) were administered and blood samples collected. Plasma retinol and retinyl esters were measured by HPLC. Tolerance curves were constructed by plotting plasma retinyl ester concentration vs time. Postprandial retinyl ester response was measured as peak rise in retinyl ester concentration and area under the curve (AUC). Peak plasma retinyl ester concentration occurred earlier for females but the earlier peak was significant only for younger subjects (< or = 50 y, P < 0.02) given the low dose and older subjects (> 50 y, P < 0.02) given the high dose. Peak rise and AUC were lower in females than in males, but this difference was significant for the high dose only (P < 0.05). In the high-dose experiment, when each age group was evaluated for sex differences the peak rise was significantly greater in males than in females in the older subjects (P < 0.05). Postabsorptive plasma retinol did not change from fasting concentrations. A lower plasma response in retinyl esters in women could be due to a more efficient chylomicron-remnant clearance.

Vitamin A metabolism: new perspectives on absorption, transport, and storage

Vitamin A metabolism: new perspectives on absorption, transport, and storage

Postprandial plasma retinyl ester response is greater in older subjects compared with younger subjects. Evidence for delayed plasma clearance of intestinal lipoproteins.

Postprandial vitamin A and intestinal lipoprotein metabolism was studied in 86 healthy men and women, aged 19-76 yr. Three independent experiments were carried out. In the first experiment, a supplement dose of vitamin A (3,000 retinol equivalents [RE]) was given without a meal to 59 subjects, aged 22-76 yr. In the second experiment, 20 RE/kg body wt was given with a fat-rich meal (1 g fat/kg body wt) to seven younger subjects (aged less than 50 yr) and seven older subjects (aged greater than or equal to 50 yr). In both experiments, postprandial plasma retinyl ester response increased significantly with advancing age (P less than 0.05). In the third experiment, retinyl ester-rich plasma was infused intravenously into nine young adult subjects (aged 18-30 yr) and nine elderly subjects (aged greater than or equal to 60 yr), and the rate of retinyl ester disappearance from plasma during the subsequent 3 h was determined. Mean (+/- SE) plasma retinyl ester residence time was 31 +/- 4 min in the young adult subjects vs. 57 +/- 8 min in the elderly subjects (P less than 0.05). These data are consistent with the concept that increased postprandial plasma retinyl ester concentrations in older subjects are due to delayed plasma clearance of retinyl esters in triglyceride-rich lipoproteins of intestinal origin.