Dr. Ron’s Research Review – September 30, 2015

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This week’s research review focuses on β-Carotene to vitamin A conversion.

β-Carotene is converted to vitamin A in the intestine by the enzyme β-carotene-15,15'-monoxygenase (BCMO1) to support vision, reproduction, immune function, and cell differentiation. (Lobo et al., 2013)
A “low converter” phenotype describes low conversion efficiency occurs after β-Carotene supplementation, reflected by the retinyl ester/ β-Carotene ratio in the chylomicron fraction. About 45% of the Western population can be classified as low converters. (Hickenbottom et al., 2002) (Lin et al., 2000)

Dr. Ron


 

Articles

Variability in conversion of beta-carotene to vitamin A in men as measured by using a double-tracer study design.
            (Hickenbottom et al., 2002) Download
BACKGROUND:  The vitamin A activity of beta-carotene is variable and surprisingly low in women. The reasons for this are not well understood. The vitamin A activity of beta-carotene in men is still uncertain. Contributions of dietary factors compared with individual traits are largely unknown. OBJECTIVE:  Our objective was to measure the intrinsic variability in the vitamin A activity of beta-carotene among healthy, well-fed men living in a controlled environment. DESIGN:  We used a double-tracer test-retest design. We dosed 11 healthy men orally with 30 micromol hexadeuterated (D6) retinyl acetate (all-trans-19,19,19,20,20,20-[2H6]retinyl acetate) and then with 37 micromol D6 beta-carotene (19,19,19,19',19',19'-[2H6]beta-carotene) 1 wk later. Doses were taken with breakfasts containing 16 g fat. We measured D6 retinol, D6 beta-carotene, and trideuterated (D3) retinol (derived from D6 beta-carotene) concentrations in plasma. Areas under the plasma concentration x time since dosing curves (AUCs) were determined for D6 retinol, D6 beta-carotene, and D3 retinol. RESULTS:  All men had detectable D6 retinol concentrations in plasma. The mean (+/-SE) absorption of D6 beta-carotene in all subjects was 2.235 +/- 0.925%, and the mean conversion ratio was 0.0296 +/- 0.0108 mol retinol to 1 mol beta-carotene. Only 6 of 11 men had sufficient plasma concentrations of D6 beta-carotene and D3 retinol that we could measure. The mean absorption of D6 beta-carotene in these 6 subjects was 4.097 +/- 1.208%, and the mean conversion ratio was 0.0540 +/- 0.0128 mol retinol to 1 mol beta-carotene. CONCLUSION:  The vitamin A activity of beta-carotene, even when measured under controlled conditions, can be surprisingly low and variable.

Variability of the conversion of beta-carotene to vitamin A in women measured by using a double-tracer study design.
            (Lin et al., 2000) Download
BACKGROUND:  Blood beta-carotene and vitamin A responses to oral beta-carotene are variable in humans. Some individuals are characterized as responders and others as low- or nonresponders. A better understanding of the conditions that produce the variability is important to help design public health programs that ensure vitamin A sufficiency. OBJECTIVE:  Our objective was to assess variability in absorption and conversion of beta-carotene to vitamin A in vivo in humans by using a novel double-tracer ¿hexadeuterated (D(6)) beta-carotene and D(6) retinyl acetate approach. DESIGN:  Eleven healthy women were housed at the US Department of Agriculture Western Human Nutrition Research Center metabolic unit for 44 d, where they consumed diets adequate in vitamins and minerals except for carotenoids. After an adaptation period, the women were given 30 micromol D(6) retinyl acetate orally, followed 1 wk later with 37 micromol D(6) beta-carotene (approximately equimolar doses). Time-dependent plasma concentration curves were determined for D(6) retinol, D(6) beta-carotene, and trideuterated (D(3)) retinol (derived from D(6) beta-carotene). RESULTS:  Mean (+/-SE) absorption of D(6) beta-carotene was 3.3 +/- 1.3% for all subjects. The mean conversion ratio was 0.81 +/- 0.34 mol D(3) retinol to 1 mol D(6) beta-carotene for all subjects. However, only 6 of the 11 subjects had plasma D(6) beta-carotene and D(3) retinol concentrations that we could measure. The mean absorption of D(6) beta-carotene in these 6 subjects was 6.1 +/- 0.02% and their conversion ratio was 1.47 +/- 0.49 mol D(3) retinol to 1 mol D(6) beta-carotene. The remaining 5 subjects were low responders with </=0.01% absorption and a mean conversion ratio of 0.014 +/- 0.004 mol D(3) retinol to 1 mol D(6) beta-carotene. CONCLUSION:  Variable absorption and conversion of beta-carotene to vitamin A both contribute to the variable response to consumption of beta-carotene. Our double-tracer approach is adaptable for identifying efficient converters of carotenoid to retinoid.

Genetics and diet regulate vitamin A production via the homeobox transcription factor ISX.
            (Lobo et al., 2013) Download
Low dietary intake of β-carotene is associated with chronic disease and vitamin A deficiency. β-Carotene is converted to vitamin A in the intestine by the enzyme β-carotene-15,15'-monoxygenase (BCMO1) to support vision, reproduction, immune function, and cell differentiation. Considerable variability for this key step in vitamin A metabolism, as reported in the human population, could be related to genetics and individual vitamin A status, but it is unclear how these factors influence β-carotene metabolism and vitamin A homeostasis. Here we show that the intestine-specific transcription factor ISX binds to the Bcmo1 promoter. Moreover, upon induction by the β-carotene derivative retinoic acid, this ISX binding decreased expression of a luciferase reporter gene in human colonic CaCo-2 cells indicating that ISX acts as a transcriptional repressor of BCMO1 expression. Mice deficient for this transcription factor displayed increased intestinal BCMO1 expression and produced significantly higher amounts of vitamin A from supplemental β-carotene. The ISX binding site in the human BCMO1 promoter contains a common single nucleotide polymorphism that is associated with decreased conversion rates and increased fasting blood levels of β-carotene. Thus, our study establishes ISX as a critical regulator of vitamin A production and provides a mechanistic explanation for how both genetics and diet can affect this process.

References

Hickenbottom, SJ, et al. (2002), ‘Variability in conversion of beta-carotene to vitamin A in men as measured by using a double-tracer study design.’, Am J Clin Nutr, 75 (5), 900-7. PubMedID: 11976165
Lin, Y, et al. (2000), ‘Variability of the conversion of beta-carotene to vitamin A in women measured by using a double-tracer study design.’, Am J Clin Nutr, 71 (6), 1545-54. PubMedID: 10837297
Lobo, GP, et al. (2013), ‘Genetics and diet regulate vitamin A production via the homeobox transcription factor ISX.’, J Biol Chem, 288 (13), 9017-27. PubMedID: 23393141