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Folate is a B vitamin that exists in either its reduced form (folate) or oxidized form (folic acid). When folate is used in this section, we are referring to the reduced form, not the vitamin itself. Another key distinction between the 2 terms is that folic acid refers to the synthetic form, while folate refers to the natural form. Folic acid is only found in certain foods because they have been fortified with it, not because they produce it. The structure of folic acid is shown below.

Another key difference between folate and folic acid is the number of glutamates in their tails. Notice that glutamate is boxed in the structure of folic acid above. Folic acid always exists as a monoglutamate, meaning it only contains 1 glutamate. On the other hand, about 90% of the folate found in foods are polyglutamates, meaning there is more than 1 glutamate in their tail. Folic acid is more stable than folate, which can be destroyed by heat, oxidation, and light2. Table 11.11 summarizes the key differences between folate and folic acid. Table 11.11 Comparison of folate to folic acid The bioavailability of folate was believed to be much lower than folic acid.3 To account for these differences, the DRI committee created dietary folate equivalents (DFEs) to set the DRIs4. DFEs are defined as follows:

The 1.7 came from research suggesting that folic acid from food was 85% bioavailable, compared to 50% for folate (85%/50% = 1.7)4. This was established in 1998 by the DRI committee, but there is newer evidence suggesting folate's bioavailability from food is higher (80% of folic acid) than previously believed3. With this data, a revised conversion factor for folic acid would be 1.25 (100%/80%). This conversion factor means that food folate levels are probably contributing more towards our dietary needs than currently being estimated by the DFE, but the DRI for folate/folic acid has not been updated. Before folate (polyglutamates) can be taken up into the enterocyte, the extra glutamates must be cleaved prior to uptake into the enterocyte by the reduced folate transporter (RFT, aka reduced folate carrier)5-7. Folic acid, because it is a monoglutamate, requires no cleavage for uptake before it is taken up through the RFT. Once inside the enterocyte, the monoglutamate form is methylated and transported into circulation through an unresolved carrier5. This series of events is depicted in the figure below.

Thus, the methylated monoglutamate form is the circulating form. This is transported to the liver where it is converted back to the polyglutamate form for storage. Folate is excreted in both the urine and feces5.

References & Links http://en.wikipedia.org/wiki/File:Folat.svg Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. Winkels R, Brouwer I, Siebelink E, Katan M, Verhoef P. (2007) Bioavailability of food folates is 80% of that of folic acid. Am J Clin Nutr 85(2): 465-473. Anonymous. (1998) Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington D.C.: National Academies Press. Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. (2006) Modern nutrition in health and disease. Baltimore, MD: Lippincott Williams & Wilkins. Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier.

The major function of folate is that it participates in 1-carbon metabolism. As described earlier, this is the transfer of 1-carbon units from 1 compound to another. The cofactor form of folate is tetrahydrofolate (THF). As is shown in the figure below, in order for THF to be formed, a methyl group is transferred to cobalamin (vitamin B12) from 5-methyl THF (THF plus a methyl group), forming methyl-cobalamin. You can see this on the left side of the figure below.

THF is a cofactor for enzymes that metabolize histidine, serine, glycine, and methionine1. The following link shows that THF is a cofactor for serine hydroxymethyltransferase, the enzyme that converts serine to glycine.

Folate deficiency affects some Americans. The hallmark symptom of folate deficiency is megaloblastic (aka macrocytic) anemia. Megaloblastic anemia, as the name suggests, is characterized by large, nucleated (most red blood cells do not have a nucleus), immature red blood cells. This occurs because folate is needed for DNA synthesis; without it red blood cells are not able to divide properly1. As a result, fewer and poorer functioning red blood cells are produced that cannot carry oxygen as efficiently as normal red blood cells2. A maternal folate deficiency can lead to neural tube defects in infants. The exact cause of neural tube defects is unknown, but folate/folic acid supplementation has been shown to decrease the incidence of neural tube defects3. The most common of these neural tube defects is spina bifida (1 out of 2500 babies born in the United States), which is a failure of the neural tube to close and the spinal cord and its fluid protrude out the infant's back, as shown below4,5.

The neural tube closes 21-28 days after conception1, and with 50% of pregnancies estimated to be unplanned, many women are not aware they are pregnant during this period1,2. It is recommended that women of childbearing age consume 400 ug of folic acid daily1. However, to expect all women to do this through supplements would likely be most difficult for those at most risk (women of low socioeconomic status, young mothers) because they might not be able to afford or not know to take the supplement. In addition, in 1998 the FDA mandated that all refined cereals and grains be fortified with 140 ug folic acid /100 grams of product7. As you can see below, spina bifida prevalence rates declined during the optional fortification years and declined further once fortification became mandatory in the United States.

The following link is an interesting account of the history that led up to the folic acid fortification. It is not clear whether folic acid fortification was fully responsible for the decrease in spina bifida rates shown above, but the rates are lower than they were pre-fortification. However, you would think that the hope was that the impact would be greater than it has been thus far. The second link is to the announcement that in 2016 the FDA approved the fortification of corn masa flour.

References & Links Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. Whitney E, Rolfes SR. (2008) Understanding nutrition. Belmont, CA: Thomson Wadsworth. Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier.

Vitamin B12 is unique among vitamins in that it contains an element (cobalt) and is found almost exclusively in animal products. Neither plants nor animals can synthesize vitamin B12. Instead, vitamin B12 in animal products is produced by microorganisms within the animal that the products came from. Animals consume the microorganisms in soil or microorganisms in the GI tract of ruminant animals produce vitamin B that can then be absorbed1. Some plant products, such as fermented soy products (tempeh, miso) and the sea algae supplement, spirulina, are advertised as being good sources of B12. However, fermented soy products are not a reliable vitamin B source2 and spirulina contains a pseudovitamin B compound that is not bioavailable3. For vegans, supplements, nutritional yeast, and fortified products like fortified soy milk can help them meet their vitamin B needs4. Vitamin B12's scientific name is cobalamin, which makes sense when you consider it contains cobalt and many amine groups, as shown in the figure below. Figure 11.21 Structure of vitamin B (cobalamin)5

The 2 cofactor forms are adenosylcobalamin and methylcobalamin. We can convert most cobalamins into these 2 cofactor forms. Most foods contain adenosylcobalamin, hydroxocobalamin, or methylcobalamin6. The most common form found in supplements is cyanocobalamin, with some also using methylcobalamin7. Cyanocobalamin is a synthetic form of vitamin B12. The uptake, absorption, and transport of vitamin B12 is a complex process. The overall bioavailability of vitamin B is believed to be approximately 50%3, with the different cobalamin forms having similar bioavailabilities7. Sublingual supplements of vitamin B have been found to be equally efficacious as oral supplements7. Excretion occurs mostly through bile, with little loss in urine6. The following descriptions and figures explain and illustrate, respectively, these processes. Vitamin B12 is normally bound to protein in food. Salivary glands in the mouth produce haptocorrin (formerly known as R protein), which travels with the food into the stomach. In the stomach, acid converts pepsinogen into pepsin, and the protein intrinsic factor is released from the parietal cells1,8.

As pepsin frees B12 from protein, haptocorrin binds to the newly freed vitamin B12 (haptocorrin + B12). Intrinsic factor escapes digestion and, along with haptocorrin + B12, exits the stomach and enters the duodenum1,8. Figure 11.23 Vitamin B in the stomach part 28,9 In the duodenum, pancreatic proteases break down haptocorrin, and again vitamin B12 is freed. Intrinsic factor then binds vitamin B12 (intrinsic factor + B12); intrinsic factor + B12 continues into the ileum to prepare for absorption1,8.

In the ileum, intrinsic factor + B12 is believed to be endocytosed by intrinsic factor binding to cubulin (aka intrinsic factor receptor), forming an endosome inside the enterocyte. Intrinsic factor is broken down in the enterocyte, freeing vitamin B12. The free vitamin B12 is then bound to transcobalamin II (TC II + B ); TC II + B moves into circulation8. Figure 11.25 Vitamin B12 absorption8,9 The liver is the primary storage site for vitamin B12. Unlike most other water-soluble vitamins, the liver is able to maintain significant stores of vitamin B12. Uptake into the liver occurs through the binding of TC II + B12 to the TC II Receptor and the endocytosis of both the compound and the receptor8. Vitamin B is once again freed after degradation of TC II. Vitamin B is primarily stored in the liver as adenosylcobalamin6,8. Figure 11.26 Hepatic uptake and storage of vitamin B 9

http://en.wikipedia.org/wiki/File:Cobalamin.png Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/ Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. (2006) Modern nutrition in health and disease. Baltimore, MD: Lippincott Williams & Wilkins. http://commons.wikimedia.org/wiki/File:Illu_small_intestine_catal%C3%A0.png

Methionine synthase is an important enzyme in 1-carbon metabolism that uses methylcobalamin as its cofactor and converts homocysteine to methionine by adding a methyl group. Methionine is then converted to other compounds that serve as methyl donors, as shown below1.

This enzyme uses adenosylcobalamin as its cofactor, and is important in the breakdown of odd chain fatty acids (5 carbons etc.). As you know, odd chain fatty acids are less common than even chain fatty acids, but this enzyme is required to properly handle these less common fatty acids1.

In addition to its role as a cofactor for enzymes, vitamin B12 is also important for preventing degradation of the myelin sheath that surrounds neurons, as shown below. Figure 11.212 Vitamin B is needed to maintain the myelin sheath that surrounds neurons2 The mechanism by which vitamin B prevents demyelination is not known3. References & Links Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. https://en.wikipedia.org/wiki/Myelin#/media/File:Neuron_Hand-tuned.svg

This is the same type of anemia that occurs in folate deficiency that is characterized by fewer, enlarged, immature red blood cells. In vitamin B12 deficiency, this can occur because there is not enough cobalamin to convert 5-methyl THF to THF as it normally would as illustrated below.

Vitamin B12 deficiency also results in nerve degeneration and abnormalities that can often precede the development of anemia. These include a decline in mental function and burning, tingling, and numbness of legs. These symptoms can continue to worsen and deficiency can be fatal1.

inadequate intrinsic factor production that causes poor vitamin B12 absorption. This condition is common in people over the age of 50 because they have the condition atrophic gastritis2. Atrophic gastritis is a chronic inflammatory condition that leads to the loss of glands in the stomach, as shown in the figure in the following link. The loss of glands leads to decreased intrinsic factor production. It is estimated that ~6% of those age 60 and over are vitamin B deficient, with 20% having marginal status3. In addition to the elderly, vegans are also at risk for vitamin B12 deficiency because they do not consume animal products. However, the deficiency may take years to develop in adults because of stores and recycling of vitamin B 2. Deficiency has the potential to occur much quicker in infants or young children on vegan diets because they do not have stores that adults do4.

As mentioned above, folate and vitamin B12 lead to the same megaloblastic (macrocytic) anemia. If high levels of folate or folic acid (most of the concern is with folic acid since it is fortified in foods and commonly taken in supplements) is given during vitamin B12 deficiency, it can correct this anemia. This is referred to as masking because it does not rectify the deficiency, but it "cures" this symptom. Folate/folic acid can do this by providing so much folate that there is enough THF for red blood cell division to occur even without having the cobalamin normally needed to accept a methyl group from 5-methyl THF. This is problematic because it does not correct the more serious neurological problems that can result from vitamin B12 deficiency. There are some people who are concerned about the fortification of cereals and grains with folic acid because people who are B12 deficient might not develop macrocytic anemia, which makes a vitamin B deficiency harder to diagnose2.

Elevated circulating homocysteine levels have been found in people with cardiovascular disease. Folate, vitamin B6, and vitamin B12 contribute to the conversion of homocysteine to methionine by providing methyl groups, thereby decreasing homocysteine concentrations, as illustrated in the figure below. Thus, based on these facts, it was hypothesized that intake of these B vitamins may decrease the risk of cardiovascular disease. Figure 11.32 One-carbon metabolism Research has found that intake of these B vitamins does decrease circulating homocysteine concentrations. However, most studies have not found that it results in improved cardiovascular disease outcomes2-4. It is debated why B vitamin intake has not resulted in improved outcomes. Some think it is because the studies have not focused on individuals with elevated homocysteine levels2, while others believe that homocysteine is a biomarker or indicator of cardiovascular disease, not a causative or contributing factor to cardiovascular disease development3. References & Links http://en.wikipedia.org/wiki/File:Homocysteine_racemic.png Abraham J, Cho L. (2010) The homocysteine hypothesis: Still relevant to the prevention and treatment of cardiovascular disease? Cleve Clin J Med 77(12): 911-918. Cacciapuoti F. (2011) Hyper-homocysteinemia: A novel risk factor or a powerful marker for cardiovascular diseases? pathogenetic and therapeutical uncertainties. J Thromb Thrombolysis 32(1): 82-88. Martai-Carvajal AJ, Sola J, Lathyris D. (2015) Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 1:CD006612.

Vitamin D is unique among the vitamins in that it is part vitamin, part hormone. It is considered part hormone for two reasons: (1) we have the ability to synthesize it, and (2) it has hormone-like functions. The amount synthesized, however, is often not enough to meet our needs. Thus, we need to consume this vitamin under certain circumstances, meaning that vitamin D is a conditionally essential micronutrient. There are two major dietary forms of vitamin D: the form produced mainly by plants and yeast is vitamin D2 (ergocalciferol), and the form mainly made by animals is vitamin D3 (cholecalciferol). The main terms in the previous sentence are because lichens, a symbiotic relationship between 2 bacteria and a fungus, are able to synthesize vitamin D3, and are being utilized some now commercially as described in the following article. The structures of these two forms are shown below. Notice that the only difference is the presence of a double bond in D2 tail that is not in D3. Figure 12.11 Structure of vitamin D (ergocalciferol) and vitamin D (cholecalciferol)1,2 We synthesize vitamin D3 from cholesterol, as shown below. In the skin, cholesterol is converted to 7-dehydrocholesterol. In the presence of UV-B light, 7-dehydrocholesterol is converted to vitamin D3. Synthesized vitamin D will combine with vitamin D-binding protein (DBP) to be transported to the liver. Dietary vitamin D2 and D3 is transported to the liver via chylomicrons and then taken up in chylomicron remnants. Once in the liver, the enzyme 25-hydroxylase (25-OHase) adds a hydroxyl (-OH) group at the 25th carbon, forming 25-hydroxy vitamin D (25(OH)D, calcidiol). This is the circulating form of vitamin D, thus 25(OH)D blood levels are measured to assess a person's vitamin D status. The active form of vitamin D is formed with the addition of another hydroxyl group by the enzyme 1alpha-hydroxylase (1alpha-OHase) in the kidney, forming 1,25 hydroxy vitamin D (1,25(OH)2D). The synthesis and activation of vitamin D is shown in the figures below. Figure 12.12 Vitamin D synthesis and activation4

Environmental Factors That Impact Vitamin D3 Synthesis Dietary or Supplemental Vitamin D Response to Low Blood Calcium Response to High Blood Calcium Vitamin D Receptor Vitamin D Deficiency, Toxicity, & Insufficiency References & Links http://en.wikipedia.org/wiki/File:Ergocalciferol.svg http://en.wikipedia.org/wiki/File:Cholecalciferol.svg Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. http://commons.wikimedia.org/wiki/File:Liver.svg https://en.wikipedia.org/wiki/Vitamin_D#/media/File:Reaction_-_cholecalciferol_to_calcidiol.png https://en.wikipedia.org/wiki/Vitamin_D#/media/File:Reaction_-_calcidiol_to_calcitriol.png Lehmann U, Hirch F, Stangl GI, Hinz K, Westphal S, Dierkes J. (2013) Bioavailability of vitamin D2 and D3 in Healthy Volunteers, a randomized placebo-controlled trial. J Clin Endocrinol Metab. 98(11): 4339-4345. Tripkovic L, Wilson LR, Hart K, Johnsen S, de Lusignan S, Smith CP, Bucca G, Penson S, Chope G, Elliott R, Hypponen E, Berry JL Lanham-New SA. (2017) Daily supplementation with 15 μg vitamin D2 compared with vitamin

Link Veggie D3 maker explores novel production process to secure future funding supplies - https:// process-to-secure-future-supplies?utm_source=newsletter_daily&utm_medium=email&utm_campaign=Newslette r%2BDaily&c=yazB%2FDHFv2VlvQJ3xinVgQ%3D%3D

The latitude a person is at affects that person's ability to synthesize vitamin D3. There is an inverse relationship between distance from the equator and UV light exposure. Thus, with increased distance from the equator (increased latitude), there is decreased UV light exposure and vitamin D3 synthesis. The link below shows the latitude and longitude lines of the United States.

Seasons also make a difference in vitamin D synthesis. In Boston (42० N), vitamin D synthesis only occurs from March-October, because during late fall and winter not enough UV-B reaches the earth's surface to synthesize vitamin D . However, in Los Angeles (34० N), vitamin D synthesis occurs year round2. The difference is the angle of the sun relative to latitude and how many UV-B photons are absorbed before they reach the earth's surface1.

Very dark skin color can provide a sun protection factor (SPF) 8-30 for those individuals who never burn2. These individuals will require approximately 5- to 10-times greater sunlight exposure than light-skinned, white individuals to synthesize the same amount of vitamin D 2,3.

Age also plays a factor in vitamin D3 synthesis. Aging results in decreased 7-dehydrocholesterol concentrations in the skin, resulting in an approximately 75% reduction in the vitamin D3 synthesis capability by age 703.

Clothing is another factor that influences vitamin D3 synthesis. More clothing means that less sun reaches your skin, and thus less vitamin D3 synthesis. Figure 12.115 Which of these 2 do you think is synthesizing less vitamin D?

There is quite a spirited debate on sunscreen, sun exposure, skin cancer, and vitamin D synthesis. On one side are the vitamin D researchers, on the other side are dermatologists. Older vitamin D research found that SPF 8 sunscreen almost totally blocked vitamin D3 synthesis4. However, more recent research as described in the article below suggests that it does occur even with sunscreen use. However, the SPF value equals 1/(# photons that reaches your skin) meaning that SPF 30 means 1/30 UV photons reach your skin. Thus, vitamin D3 synthesis shouldn't be totally blocked. In addition, studies indicate that consumers apply 1/2 or less of the amount required to get the listed SPF protection4. Researchers recommend sun exposure on the face, arms, and hands for 10-15 minutes 2-3 times per week between 10 AM-3 PM2,5. However, dermatologists do not like "sensible sun exposure" because this is also the peak time for harmful sun exposure. Dermatologists say that "sensible sun exposure" appeals to those who are looking for a reason to support tanning and are at highest risk (primarily young, fair-skinned females) of sun damage. They argue that vitamin D can be provided through supplementation3. What about tanning beds? Not all tanning beds provide UV-B rays that are needed for vitamin D3 synthesis. In fact, some advertise that they only use UV-A rays that are safer, even though this is not the case6. Virtually every health organization advises against using tanning beds, because the risks are far greater than the potential benefits6,7.

However, there are a limited number of foods naturally rich in vitamin D. Good sources of vitamin D are fatty fish (salmon, tuna, etc.) and their oils (such as cod liver oil). The amount of vitamin D in fatty fish varies greatly with wild-caught salmon being the highest. One study showed that farmed salmon contained almost 75% less vitamin D than wild-caught salmon1. It is not known whether this disparity exists between other types of farmed and wild-caught fish varieties.

Thus, since not many foods contain vitamin D, cow’s milk has been voluntarily fortified with vitamin D2 or D3 (100 IU/8 oz) since the 1930s3. However, the actual measured amount of vitamin D in many brands of cow’s milk is far less than stated on their labels4,5. Part of this problem stems from a lack of a standardized method for measuring vitamin D in the past. Without standardized analysis, there inevitably was a wide range of variation from lab-to-lab in the reported amount of vitamin D. Another issue with relying on dairy products to provide vitamin D is the common problem of lactose intolerance. Lactose intolerant individuals don't have lactase, the enzyme needed to break down lactose. Common symptoms of this condition include:

Thus, you can see that many people are lactose intolerant. Coincidentally, many of these people have darker pigmented skin, meaning that they have an increased risk of vitamin D deficiency/insufficiency because they require greater sun exposure to synthesize adequate amounts of vitamin D3. Other foods that are sometimes fortified are breakfast cereals and orange juice. Despite the fact that orange juice doesn't contain fat, and vitamin D is fat-soluble, vitamin D is quite bioavailable in orange juice10.

References & Links Lu Z, Chen TC, Zhang A, Persons KS, Kohn N, et al. (2007) An evaluation of the vitamin D3 content in fish: Is the vitamin D content adequate to satisfy the dietary requirement for vitamin D? J Steroid Biochem Mol Biol 103(3-5): 642. Anonymous. (1997) Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, D.C.: National Academies Press. Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier. Holick MF, Shao Q, Liu WW, Chen TC. (1992) The vitamin D content of fortified milk and infant formula. New England Journal of Medicine, the 326(18): 1178. Faulkner H, Hussein A, Foran M, Szijarto L. (2000) A survey of vitamin A and D contents of fortified fluid milk in ontario. J Dairy Sci 83(6): 1210.

McBean LD, Miller GD. (1998) Allaying fears and fallacies about lactose intolerance. J Am Diet Assoc 98(6): 671. Tangpricha V, Koutkia P, Rieke S, Chen T, Perez A, et al. (2003) Fortification of orange juice with vitamin D: A novel approach for enhancing vitamin D nutritional health. Am J Clin Nutr 77(6): 1478. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

One of the major functions of vitamin D is to assist in maintaining blood calcium concentrations. The other major regulators of blood calcium concentrations are 2 hormones: parathyroid hormone (PTH) and calcitonin, which are released from the parathyroid glands and thyroid glands, respectively. Bone serves as the calcium depot, or reservoir, if there is a sufficient concentration in the body. In bone, calcium is found in hydroxyapatite crystals on a collagen matrix.

Calcium and phosphorus are either jointly deposited (deposition) or jointly liberated (resorption) from bone hydroxyapatite to maintain/achieve blood calcium concentrations. Osteoblasts are bone cells that are responsible for bone formation or depositing hydroxyapatite. Osteoclasts are the bone cells that are responsible for breaking down or resorption of bone. An easy way to remember the function of these cells is:

The parathyroid senses low blood calcium concentrations and releases PTH. These steps are designed to maintain consistent blood calcium concentrations, but also affects phosphate (phosphorus) concentrations. PTH has 3 effects:

The second effect of PTH is decreased calcium excretion in urine. This is a result of increased calcium reabsorption by the kidney before it is excreted in urine. Kidney phosphate reabsorption is decreased, meaning the net effect is less calcium, but more phosphate in urinary excretion, as shown in the figure below.

The 3rd effect of PTH is that it increases 1,25(OH)2D activation in the kidney, by increasing 1alpha-hydroxylase levels. The 1,25(OH)2D then increases calcium and phosphorus absorption in the small intestine to help raise blood calcium levels, as shown below. This mechanism will be discussed in more detail in the vitamin D receptor subsection.

Overall PTH causes more calcium and phosphate to be leached from bone, and absorbed from the intestine into the blood. Coupled with decreased calcium and increased phosphate urinary excretion, means that blood calcium levels rise without a marked rise in phosphate levels, as depicted in the figure below. Figure 12.134 1,25(OH)2D increased calcium and phosphorus absorption3 References & Links Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Whitney E, Rolfes SR. (2011) Understanding nutrition. Belmont, CA: Wadsworth Cengage Learning. http://en.wikipedia.org/wiki/File:Illu_thyroid_parathyroid.jpg

In adults, it is rare for blood calcium concentrations to get too high. However, in infants and young children whose bodies, and thus bones, are not as large, the hormone calcitonin helps to prevent blood calcium levels from getting too high1.

High blood calcium concentrations are sensed by the thyroid, which releases calcitonin. This response is designed to maintain/achieve normal blood calcium concentrations, but also affects phosphate (phosphorus) levels. Calcitonin has 3 effects1,2:

The third effect of calcitonin is to decrease 1alpha-hydroxylase levels, which decreases the activation of 1,25(OH)2D. As a result, the absorption of calcium and phosphorus from the small intestine is decreased, as shown below.

Overall, calcitonin inhibits the 3 actions that PTH uses to increase blood calcium levels. Thus, more calcium and phosphate are deposited into bones and excreted into urine as shown below. This causes blood calcium levels to decrease.

References & Links Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Whitney E, Rolfes SR. (2011) Understanding nutrition. Belmont, CA: Wadsworth Cengage Learning http://en.wikipedia.org/wiki/File:Illu_thyroid_parathyroid.jpg

Vitamin D, along with vitamin A, are unique among the vitamins in that they have nuclear receptors. Many steroid hormones have nuclear receptors. The following figure illustrates the action of a nuclear hormone receptor.

In the figure above of the hormone (in this case thyroid hormone) receptor, the receptor’s ligand (something that binds to the receptor), enters the nucleus and binds to the thyroid hormone receptor (TR). The TR has paired (formed a dimer) with the retinoid X receptor (RXR) on the hormone response element (HRE) in the promoter (region before a gene in the DNA sequence) of target genes. The HRE for thyroid hormone is the thyroid hormone response element. Target genes are those whose transcription is altered by the hormone binding to its receptor on the response element. The mRNA produced then leaves the nucleus where it is translated into protein.

1,25(OH)2D is considered to be the active form of vitamin D because it binds to the vitamin D receptor (VDR). Like the thyroid hormone example above, there is a vitamin D response element (VDRE) in the promoter of specific vitamin D target genes. In the figure below, 25(OH)D, the major circulating form of vitamin D, is usually transported through the blood to a target tissue by vitamin D binding protein (DBP). The kidney converts 25(OH)D to 1,25(OH)2D by use of the enzyme 1alpha-hydroxylase, but this enzyme is also found in other tissues to synthesize 1,25(OH)2D primarily for their own use (rather than secreting like the kidney). The latter scenario is what is being represented in the in figure below. 1,25(OH)2D (bound to DBP) moves from the kidney, or the tissue itself, into the nucleus. It then binds to the vitamin D receptor (VDR), that is dimerized to the RXR on the vitamin D response element of the target gene. Consequently, this binding causes an increases transcription of mRNA. The mRNA then moves into the cytoplasm to synthesize specific proteins. This process is shown in the figure below.

It's through this action that 1,25(OH)2D is able to increase calcium absorption. In this case, the target gene is the calcium-binding protein calbindin. Thus, increased 1,25(OH)2D leads to increased calbindin mRNA. This then leads to increased calbindin protein levels. Calbindin will be discussed in more detail in the calcium section.

Rickets is a vitamin D deficiency condition in infants and children. A lack of vitamin D leads to decreased bone mineralization, causing the bones to become weak. The bones then bow under pressure, leading to the characteristic bowed legs, as seen below.

While rickets and osteomalacia are fairly rare in the United States, it is believed that vitamin D insufficiency might be much more widespread. Insufficiency means that the level of intake, or body status, is suboptimal (neither deficient nor optimal). The figure below illustrates this concept. Figure 12.163 Illustration of insufficient or suboptimal levels Suboptimal/insufficient means intake, or status, is higher than deficient, but lower than optimal. This is an important distinction to understand particularly for vitamin D, because there have been some (like Dr. Michael Holick described in the link below) saying the people are vitamin D deficient when their circulating 25(OH)D concentrations are lower than optimal. This is different from a classical deficiency definition, where there is a condition associated with too low level of intake or body status. What is really being described is that circulating 25(OH)D concentrations might be suboptimal. A lot of the debate about vitamin D deficiency is nicely captured in the article about Dr. Michael Holick, a prominent vitamin researcher. Thus, higher intake levels will provide additional benefits. The functions of vitamin D are growing by the day due to increased research discoveries. These functions now include benefits beyond bone health, further supporting the importance of vitamin D. In late 2010, an RDA for vitamin D was established (was an Adequate Intake before). This made it, along with calcium, the first micronutrients to have their DRIs revised4. The RDA for vitamin D is 3 times higher than the previous AI. Many believe these are more reasonable levels, while others think that the new RDA is still not high enough. This belief, that many people’s vitamin D intake/status is suboptimal, is challenged by a review described in the first link below that found that vitamin D did not reduce osteoporosis risk. In addition, a recent meta-analysis (second link) concluded that “there is probably no benefit to expect from vitamin D supplementation in normally healthy people.” Vitamin D from supplements can become toxic. You cannot develop vitamin D toxicity from sun exposure, because the sunlight degrades a precursor of vitamin D in the skin5. Vitamin D toxicity results in hypercalcemia or high blood calcium levels. These become problematic because it can lead to calcification of soft tissues. References & Links http://en.wikipedia.org/wiki/File:Rickets_USNLM.gif http://en.wikipedia.org/wiki/File:XrayRicketsLegssmall.jpg Whitney E, Rolfes SR. (2011) Understanding nutrition. Belmont, CA: Wadsworth Cengage Learning.

Calcium is taken up into the enterocyte through Transient Receptor Potential V6 (TRPV6), a calcium channel found on the brush border. Calbindin is the calcium binding protein that facilitates uptake through TRPV6 and transport across the enterocyte. Ca2+-Mg2+ ATPase functions to pump calcium out of the enterocyte and into circulation and to pump magnesium into the enterocyte, as shown below1.

As we have previously discussed, increased 1,25(OH)2D synthesis in the kidney causes increased binding to the vitamin D receptor, which increases calbindin synthesis. Increased calbindin ultimately increases calcium uptake and absorption.

There are a couple of calcium-binding compounds that inhibit its absorption (normally by binding to it). Therefore, even though some foods are good sources of calcium, the calcium is not very bioavailable. Oxalate, found in high levels in spinach, rhubarb, sweet potatoes, and dried beans, is the most potent inhibitor of calcium absorption2. Recall that calcium oxalate is one of the compounds that makes up kidney stones. Based on this understanding, it should not be a surprise that formation of this compound inhibits calcium absorption.

References & Links Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. (2006) Modern nutrition in health and disease. Baltimore, MD: Lippincott Williams & Wilkins. http://en.wikipedia.org/wiki/File:Calcium_oxalate.png http://en.wikipedia.org/wiki/File:Phytic_acid.png

Calcium bioavailability varies greatly from food to food, as shown in the table below. This table gives the serving size, calcium content of that food, and percent absorbed. The calcium content is multiplied by the absorption percentage to calculate the estimated calcium absorbed. Finally, it shows servings of each food needed to equal the estimated calcium absorbed from 1 serving of milk.

The 2 most common forms of calcium found in supplements are calcium carbonate and calcium citrate. As you can see in the figure below, they differ in the amount of elemental calcium they contain. This shows how much of the molecular weight of the compound is calcium.

The higher the percent elemental calcium, the greater the amount of calcium you will receive per given weight of that compound, versus a compound that has a lower elemental calcium percentage. Both carbonate and citrate forms are well absorbed, but individuals with low stomach acid absorb citrate better. Also, carbonate is best absorbed when taken with food, while for citrate it is equally well absorbed when taken alone4. Older research suggested that calcium citrate malate was more bioavailable than other calcium sources. However, a more recent clinical study found no difference in the bioavailability of calcium from calcium citrate malate in orange juice, skim milk, or calcium carbonate supplements5. There is some evidence that suggests that even though bioavailability is the same among these different forms, they might not be equally effective in improving bone measures6.

Martini L, Wood R. (2002) Relative bioavailability of calcium-rich dietary sources in the elderly. Am J Clin Nutr 76(6): 1345-1350. Weaver C, Janle E, Martin B, Browne S, Guiden H, et al. (2009) Dairy versus calcium carbonate in promoting peak bone mass and bone maintenance during subsequent calcium deficiency. Journal of Bone and Mineral Research

There are also a number of non-bone functions of calcium. Calcium is an intracellular signaling molecule. Because of this, intracellular calcium is tightly controlled, primarily stored within organelles.

Neurotransmitter release is stimulated by the opening of voltage-gated Ca2+ channels. This stimulates the synaptic vesicle to fuse with the axon membrane and release the neurotransmitter into the synapse, as shown below1. Figure 12.231 Calcium regulates neurotransmitter release2

Calcium is released in muscle cells, where it binds to the protein troponin, changes its shape, and removes the tropomyosin blockade of actin active sites so that contraction can occur3. This can be seen in the following animation and figure (same link).

Calcium acts as an intracellular messenger for the release of hormones, such as insulin. The link below shows how in the beta cells of the pancreas, the opening of voltage-gated calcium channels stimulates the insulin granules to fuse with the beta cell membrane to release insulin.

References & Links Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. http://en.wikipedia.org/wiki/File:Synapse_Illustration_unlabeled.svg 3. 4. Figure adapted from: Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing.

Because of the large amount of calcium in bones (which can be mobilized), deficiency is rare1. Hypocalcemia (low serum blood calcium concentrations) can result in tetany (involuntary muscle contractions)2. In addition, calcium deficiency in children can lead to rickets, the same as occurs in vitamin D deficiency. While not a deficiency, low calcium intake can lead to decreased bone mineral density and the conditions osteopenia and osteoporosis. How these differ from osteomalacia and normal bone is illustrated and described below. There are two different bone components that we will consider to understand what is happening in the bone. Matrix is the protein scaffolding (primarily collagen) onto which mineral is deposited. Mineral is simply the mineral deposited on the matrix. Figure 12.241 Bone states; the width of each figure represents the bone mass. The height of the matrix and mineral boxes represents the relative proportion for matrix to mineral in the bone. Adapted from reference 3.

To prevent osteoporosis it is important to build peak bone mass (the maximum amount that a person will have in their lifetime), 90% of which is built by age 18 and 20 in females and males, respectively, but can continue to increase until age 30. After that time, bone mass starts to decrease. For women after menopause, bone mass decreases dramatically because of the decrease in estrogen production, as shown in the link below5. There is a decrease after menopause in women (estrogen stimulates osteoblasts), that results in a steep decrease in bone mass. Combined with the fact that women have lower peak bone mass to begin with, helps further explain why osteoporosis is more common in females. A measure of bone status is bone mineral density. As the name indicates, bone mineral density is a measure of the amount of mineral in bone. Dual energy X-ray absorptiometry (DEXA) accurately measures bone mineral density using a small amount of radiation. A DEXA is shown in the figure below. Figure 12.242 DEXA scanner6

From the scan, a bone mineral density t-score is generated. These measure your peak bone density compared to a healthy 30-year old adult and give you values of how much higher or lower you are7. The following table summarizes the levels and their scores.

This DEXA measurement cannot distinguish whether the low bone mineral density is due to too little bone (osteoporosis) or too little mineral (osteomalacia)8. There are other methods of measuring bone mineral density, such as peripheral DEXA and ultrasound. These typically are done on the wrist or heel, but are not as accurate because that one area might not reflect the bone mineral density in other parts of the body9. Calcium toxicity is rare, occurring in those with hyperparathyroidism or high calcium supplementation levels. Like vitamin D, toxicity can lead to calcification of soft tissues9. In addition, a very high intake of calcium can lead to kidney stone formation. References & Links Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. (2006) Modern nutrition in health and disease. Baltimore, MD: Lippincott Williams & Wilkins. Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Sambrook, P. Bone structure and function in normal and disease states

You have already learned about how blood phosphate levels are regulated in the body by PTH, calcitonin, and 1,25(OH)2D. Animal products are rich sources of phosphate. Plant products contain phosphorus, but some is in the form of phytic acid (phytate, these names are used interchangeably). In grains, over 80% of the phosphorus is phytate. This structure is shown below1.

The bioavailability of phosphorus from phytate is poor (~50%) because we lack the enzyme phytase that would cleave the phosphorus so it can be taken up3. Phytate binds to other minerals and decreases our ability to absorb them (you have learned that it is an inhibitor of calcium uptake, you will learn about it binding other minerals in subsequent sections). Nevertheless, ~50-70% of dietary phosphorus is absorbed1. Another source of phosphorus is phosphoric acid that is used to acidify colas. Colas are caramel-colored, carbonated soft drinks that contain caffeine, such as Coca-Cola, Pepsi, etc. Epidemiological studies have found that soft drink consumption is associated with decreased bone mineral densities, particularly in females4,5. It has been hypothesized that phosphoric acid plays some role in this effect, but there is limited evidence to support this belief.

Phosphorus deficiency is rare, but can hinder bone and teeth development. Other symptoms include muscle weakness, rickets, and bone pain6. Toxicity is also rare, but it causes low blood calcium concentrations and tetany1.

Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. http://en.wikipedia.org/wiki/File:Phytic_acid.png Phosphorus. Linus Pauling Institute Micronutrient Information Center. Tucker K, Morita K, Qiao N, Hannan M, Cupples LA, et al. (2006) Colas, but not other carbonated beverages, are associated with low bone mineral density in older women: The framingham osteoporosis study. Am J Clin Nutr 84(4): 936-942. Libuda L, Alexy U, Remer T, Stehle P, Schoenau E, et al. (2008) Association between long-term consumption of soft drinks and variables of bone modeling and remodeling in a sample of healthy german children and adolescents. Am J Clin Nutr 88(6): 1670-1677. Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill.

References & Links Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. http://commons.wikimedia.org/wiki/File:Popc_details.svg http://en.wikipedia.org/wiki/File:DNA_chemical_structure.svg http://en.wikipedia.org/wiki/File:ATP_structure.svg

Fluoride is a nonessential mineral. It is not required by the body and it is not widely found in the food supply. The majority of what we consume comes from fluoridated water. Other good non-dietary sources are fluoridated toothpaste and dental rinses1. Absorption of fluoride is near 100% for both dietary and non-dietary forms and it is rapidly excreted in the urine2. Fluoride alters the mineralization of bones and teeth. It does this by replacing hydroxyl (OH) ions in hydroxyapatite (Ca10(PO4)6(OH)2) , forming fluorohydroxyapatite. Fluorohydroxyapatite is more resistant to acid degradation than hydroxyapatite, leading to fewer cavities2. Since it is a nonessential mineral, there is no fluoride deficiency, but lower levels are associated with higher dental cavity rates. This connection is why so many water supplies are fluoridated. However, fluoride can be quite toxic. Acute toxicity symptoms from large intakes of fluoride include1:

There is debate as to whether water should be fluoridated. The following links are examples of just how conflicted the U.S. is. The first is a New York Times article on this topic. There is also an article about Portland’s decision to begin fluoridating its water in 2014. The third article is about a bill introduced by a Kansas lawmaker concerned about the effects of water fluoridation. Salina, Kansas, which is home to one of Kansas State University’s campuses, voted last November to not rescind its policy of fluoridating its water, as described in the fourth link. References & Links Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. http://en.wikipedia.org/wiki/File:Fluorosisb%26a.jpg https://en.wikipedia.org/wiki/Dental_fluorosis#/media/File:FluorosisFromNIH.jpg Beltran-Aguilar, ED, Barker, L, Dye, BA. (2010) Prevalence and Severity of Dental Fluorosis in the United States, 1999-2004.

Another form of vitamin K, menaquinone (K2), is synthesized by bacteria in the colon (and potentially elsewhere). Menaquinone comprises ~10% of absorbed vitamin K every day and can also be found in small amounts in animal products. Its structure is shown below3. Figure 12.52 Structure of menaquinone (K2). Menaquinones have side chains of varying length4

Vitamin K is absorbed like other fat-soluble substances. Approximately 80% of phylloquinone and menaquinone are incorporated into chylomicrons and stored primarily in the liver2,6. Once metabolized, vitamin K is primarily excreted via bile in the feces, with a lesser amount excreted in urine6.

References & Links http://en.wikipedia.org/wiki/File:Phylloquinone_structure.svg McGuire M, Beerman KA. (2011) Nutritional sciences: From fundamentals to food. Belmont, CA: Wadsworth Cengage Learning. Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. http://en.wikipedia.org/wiki/File:Menaquinone.svg http://en.wikipedia.org/wiki/File:Menadione.png Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing.

The enzyme, gamma-glutamyl carboxylase, uses a vitamin K cofactor to convert glutamic acid to gamma-carboxyglutamic acid (Gla). In the process of serving as a cofactor, vitamin K is converted to vitamin K epoxide (structure in the figure below).

Vitamin K epoxide needs to be converted back to vitamin K to serve as a cofactor again. Gla proteins are those that contain gamma-carboxyglutamic acid(s). This formation of gamma-carboxyglutamic acid allows the 2 positive charges of calcium to bind between the 2 negative charges on the carboxylic acid groups (COO-) in the Gla. The binding of calcium activates these proteins3-5. Figure 12.513 Gamma-glutamyl carboxylase converts glutamic acid (left) to gamma-carboxyglutamic acid (Gla, right). Proteins containing gamma-carboxyglutamic acid are known as Gla proteins. Binding of calcium activates Gla proteins. After being used as a cofactor by gamma-glutamyl carboxylase to produce a Gla protein, vitamin K becomes vitamin K epoxide. Vitamin K epoxide needs to be converted back to vitamin K to serve as a cofactor again. Activated Gla proteins are important in blood clotting. Blood clotting occurs through a cascade of events, as shown in the following video. The animation below gives an overview of blood clotting, the video is a fun depiction of the blood clotting cascade.

If these proteins within the blood clotting cascade are not activated Gla proteins, the cascade does not proceed as normal, leading to impaired blood clotting. Warfarin (Coumadin) and dicumarol are a couple of blood thinning drugs that inhibit this regeneration of vitamin K. This reduces the amount of activated Gla proteins in the blood clotting cascade, thus reducing the clotting response. The structure of warfarin and dicumarol are shown below6. Figure 12.515 Structure of warfarin8

Vitamin K may also be important for bone health. There are 3 Gla proteins found in bone: osteocalcin, matrix Gla protein (MGP), and protein S7. Osteocalcin is a major bone protein, constituting 15-20% of all non-collagen proteins in bone. However, overall, the function of these 3 proteins in bone is not known3,4. Some research suggests that higher vitamin K status or intake decreases bone loss, but it is still not clear how important vitamin K is for bone health10. References & Links https://en.wikipedia.org/wiki/Glutamic_acid#/media/File:Glutamic_Non-ionic.png https://commons.wikimedia.org/wiki/File:Vitamin-K-Epoxid.svg Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. McGuire M, Beerman KA. (2011) Nutritional sciences: From fundamentals to food. Belmont, CA: Wadsworth Cengage Learning. http://en.wikipedia.org/wiki/File:Coagulation_full.svg Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. (2006) Modern nutrition in health and disease. Baltimore, MD: Lippincott Williams & Wilkins. http://en.wikipedia.org/wiki/File:Warfarin.svg http://en.wikipedia.org/wiki/File:Dicumarol.svg Shea MK, Booth S. (2008) Update on the role of vitamin K in skeletal health. Nutr Rev 66(10): 549-557.

Vitamin K deficiency is rare, but can occur in newborn infants. They are at higher risk, because there is poor transfer of vitamin K across the placental barrier (from mother to fetus in utero), their gastrointestinal tracts do not contain vitamin K producing bacteria, and breast milk is generally low in vitamin K (most infant formula is fortified)1. As a result, it is recommended (and widely practiced) that all infants receive a vitamin K injection within 6 hours of birth2. Prolonged antibiotic treatment (which kills bacteria in the gastrointestinal tract, including those that produce menaquinone) and lipid absorption problems can also lead to vitamin K deficiency3. Vitamin K deficient individuals have an increased risk of bleeding or hemorrhage. Recall that high levels of alpha-tocopherol intake (levels that generally would only be achieved through supplementation) can also interfere with vitamin K's blood clotting function. It is believed that an alpha-tocopherol metabolite, with similar structure to the vitamin K forms you learned about, antagonizes the action of vitamin K.

References & Links Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing. Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw's perspectives in nutrition. New York, NY: McGraw-Hill. McGuire M, Beerman KA. (2011) Nutritional sciences: From fundamentals to food. Belmont, CA: Wadsworth Cengage Learning.

There are 3 forms of vitamin A (retinol, retinal, and retinoic acid) that collectively are known as retinoids. Retinol is the alcohol (OH) form, retinal is the aldehyde (COH) form, and retinoic acid is the carboxylic acid (COOH) form, as shown in the figure below (areas of difference are indicated by red).

Among these different retinoids, retinol and retinal are fairly interchangeable. Either form is readily converted to the other. However, only retinal is used to form retinoic acid, and this is a one-way reaction. Thus, once retinoic acid is formed it can't be converted back to retinal, as shown in the figure below.

Preformed vitamin A means that the compound is a retinoid. Preformed vitamin A is only found in animal products (carrots are not a good source of preformed vitamin A). Most retinol in animal products is esterified, or has a fatty acid added it, to form retinyl esters (aka retinol esters). The most common retinyl ester is retinyl palmitate (retinol + the fatty acid palmitate) whose structure is shown below.

Provitamin A is a compound that can be converted to vitamin A in the body, but currently is not in vitamin A form. The next section will talk about carotenoids, some of which are provitamin A compounds. International units are also used for vitamin A, such that: 1 IU = 0.3 ug retinol or 0.6 ug beta-carotene Subsections: Carotenoids Vitamin A Uptake, Absorption, Transport & Storage Vitamin A Nuclear Receptors Vitamin A Functions Vitamin A Deficiency & Toxicity

Carotenoids are 40-carbon compounds that are found throughout nature. Animals do not produce carotenoids, thus any found in animals (including people) come from consumed plants or microorganisms. There are more than 600 natural carotenoids. However, the 6 main ones found in the diet and in the body are1:

Carotenoids can be further classified as provitamin A or non-provitamin A. Provitamin A carotenoids are those that can be cleaved to form retinal, while the non-provitamin A carotenoids cannot. The structure and classification of the 6 major carotenoids are shown below.

After provitamin A carotenoids are taken up into the enterocyte, some are cleaved to form retinal. In the case of symmetrical beta-carotene, it is cleaved in the center to form 2 retinal molecules as shown below. Figure 12.612 Cleavage of beta-carotene 2 to retinal molecules2

To help account for the fact that retinol can be made from carotenoids, the DRI committee made retinol activity equivalents (RAE) that take into account the bioavailability and bioconversion of provitamin A carotenoids.

Supplemental beta-carotene is much more bioavailable than dietary beta-carotene found in a natural matrix within plant food components. As a result, you need to consume 6 times more dietary beta carotene to have the same RAE value as supplemental beta-carotene. The RAE difference between the provitamin A carotenoids is due to beta-carotene being cleaved to form 2 retinals, where alpha-carotene and beta-cryptoxanthin are cleaved 1 retinal. As a result, twice as much dietary alpha-carotene and beta-cryptoxanthin needs to be consumed to have the same RAE value as dietary beta-carotene. References & Links Lindshield BL, Erdman JW. (2006) Carotenoids. In: Bowman BA, Russell RM, editors. Present Knowledge in Nutrition. Washington, D.C.: International Life Sciences Institute. pp. 184-197.r https://en.wikipedia.org/wiki/Retinal#/media/File:All-trans-Retinal2.svg Anonymous. (2001) Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, D.C.: National Academies Press.

Esters are removed by esterases so that free retinol can be taken up into the enterocyte. Preformed vitamin A is highly bioavailable (70-90%) if consumed with some fat2. Carotenoids have a much lower bioavailability, which varies based on the carotenoid and matrix it is in when consumed. Once provitamin A carotenoids are taken up into the enterocytes, they are: (1) cleaved to retinal and then converted to retinol or (2) absorbed intact and incorporated into chylomicrons. Retinol in the enterocyte is esterified, forming retinyl esters. Retinyl esters are packaged into chylomicrons (CM) and enter the lymph system. Once the chylomicrons reach circulation, triglycerides are cleaved off to form chylomicron remnants (CM Rem). These are taken up by hepatocytes, where the retinyl esters are de-esterified to form retinol. The liver is the major storage site of vitamin A. For storage, the retinol will be transported from hepatocytes to stellate cells and converted back to retinyl esters, the storage form of vitamin A.

protein (RBP). Retinol + RBP are then bound to a large transport protein, transthyretin (TTR). It is believed that retinol + RBP would be filtered out by the kidney and excreted in urine if it was not bound to TTR1.

References & Links Stipanuk MH. (2006) Biochemical, physiological, & molecular aspects of human nutrition. St. Louis, MO: Saunders Elsevier.Stipaunuk Gropper SS, Smith JL, Groff JL. (2008) Advanced nutrition and human metabolism. Belmont, CA: Wadsworth Publishing.