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them extra vitamin A.  research in the 1930s found that over 90 percent of  are three times more likely to have low vitamin
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                 people with kidney stones were deficient in vitamin A.  Kidney stones can  D levels than non-obese controls.  thus, finding
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                 be induced in animals by feeding doses of vitamin D that are insufficient  markers indicating vitamin A overload is more
                 to cause abnormally high calcium levels,  suggesting that they are the first  likely to reflect the poor vitamin D status of most
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                 and most sensitive marker of vitamin D toxicity. vitamin A is capable of  Americans and the exceptionally poor vitamin
                 completely protecting against vitamin D-induced kidney calcification. 24   D status of obese Americans than it is to reflect
                 Perhaps such a small amount of vitamin D increased the risk of kidney  a supposed excess of vitamin A in the standard
                 stones in this elderly population because its members were being advised  American diet.
                 to avoid vitamin A.                                                Vitamin A deficiency has been associated
                                                                                with a number of prevalent diseases, including
                 Are viTAMin A inTAKeS exCeSSive?                               childhood  asthma, 43,44   kidney  stones  formed
                    One of the co-authors of the Cannell paper conducted a study, which  spontaneously from calcium phosphate,  and fatty
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                 has not yet been published, showing that four percent of obese Wisconsin  liver disease.  vitamin A in doses above those
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                 adults had blood markers indicating their livers were overloaded with vi-  needed to prevent deficiency protects against
                 tamin A.  vitamin D mobilizes vitamin A from the liver and increases its  oxidative stress,  kidney stones formed from
                        1
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                 utilization,  so vitamin A overload is most likely to occur in people with  dietary oxalate,  and exposure to environmental
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                 low vitamin D status. At least half of all Americans and over 80 percent of  toxins. 47
                 African Americans have low vitamin D levels.  Morbidly obese patients     The vitamin A rDA is 3,000 iU for adult
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                                               GeTTInG TecHnIcAl wITH VITAMInS A AnD D

                       Vitamins A and D are both precursors to nuclear hormones, which are molecules that bind to receptors, travel into
                   the nucleus, bind to DnA of specific target genes, and control the expression of those genes. Vitamin A is activated in a
                   two-step process in which it is converted first from retinol into retinaldehyde and then from retinaldehyde into all-trans
                   retinoic acid (ATRA). Similarly, vitamin D is activated in a two-step process in which it is converted first from cholecalcif-
                   erol to calcidiol and then from calcidiol to calcitriol. Retinoic acid binds to several types of retinoic acid receptors (RARs)
                   while calcitriol binds to the vitamin D receptor (VDR).
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                       In order to bind to DnA and control gene expression, RARs and the VDR must partner up with another receptor
                   called the retinoid X receptor (RXR). These partners bind to each other to form a two-unit receptor complex called a
                   dimer. Since the two receptors that form the dimer are different from one another, the complex is called a heterodimer
                   and the process of binding together is called heterodimerization. The RXR heterodimerizes with many other nuclear re-
                   ceptors as well, such as the thyroid hormone receptor and the steroid hormone receptors. The heterodimers then travel
                   to the nucleus, bind to DNA, and recruit either coactivators that help a gene start making a protein or corepressors that
                   stop the gene from making a protein. 31
                       Researchers agree ATRA must bind RAR and calcitriol must bind VDR for this process to begin, but they debate
                   whether the RXR is simply a “silent partner” or whether it too must be bound by a hormone. A second derivative of vita-
                   min A called 9-cis-retinoic acid (9cRA) is the hormone that binds to and activates the RXR in test tube studies, but some
                   scientists have claimed that 9CRA does not exist in the live animal. In 1992, Heyman and colleagues isolated 9CRA from
                   animal tissues,  while other researchers using different techniques more recently were unable to find any. 33,34  Large doses
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                   of vitamin A produce high tissue concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid, a probable breakdown prod-
                   uct of 9CRA.  Hormones that bind to the heterodimeric partners of the RXR such as activated vitamin D,  which binds
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                   the VDR, and clofibrate, which binds to PPAR-α,  decrease levels of vitamin A stored in the liver. Rosiglitazone, which
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                   binds to PPAR-γ, another RXR heterodimeric partner, ramps up the activation of retinol to ATRA.  ATRA spontaneously
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                   converts to 9CRA when exposed to the endoplasmic reticulum, one of the organelles present within every cell.  Taken
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                   together, these findings suggest that vitamin D and other signaling compounds whose receptors heterodimerize with the
                   RXR mobilize stored vitamin A from the liver and increase its conversion to 9CRA so that it can be used in cooperative
                   signaling processes.
                       In 2006, researchers from Spain showed that 9cRA must bind to the RXR in order for the calcitriol-VDR-RXR com-
                   plex to bind to DNA and control gene expression. More recently, the same group showed that when calcitriol binds to
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                   the VDR, it recruits corepressors that will cause it to suppress the expression of its target genes, but when 9cRA binds
                   to the complex, the corepressors are released, allowing it to activate the expression of its target genes. 40
                       In plain English, this means that vitamins A and D are not antagonists but actually cooperate with one another to
                   carry out their functions.
                 22                                         Wise Traditions                                 SPRING 2009
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