Transcript Slide 1 - Elsevier

Chapter 13
Vitamin D: Biology, Actions, and
Clinical Implications
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FIGURE 13.1 Pathway of native hormone or 1α,25-dihydroxyvitamin D3 production. The major source of vitamin
D3 is through ultraviolet irradiation of 7-dehydrocholesterol in the skin. The liver 25-hydroxylase enzyme
(encoded by CYP2R1) then converts vitamin D3 to 25-hydroxyvitamin D3 (25-OH-D3), the major circulating form
of the vitamin. Generation of 1α,25-dihydroxyvitamin D3 occurs primarily in the kidney by the 25-OH-D-1αhydroxylase enzyme (encoded by CYP27B1). See text for more details. Source: Plum and DeLuca (2010). Nat
Rev Drug Discov 9(12):941–55.
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FIGURE 13.2 Overview of the vitamin D metabolic pathway.
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FIGURE 13.3 Regulation of 1α-hydroxylase in the kidney. Low levels of calcium stimulate the secretion of
parathyroid hormone (PTH) from parathyroid glands as shown in the top of the figure. PTH then binds to its
receptor (PTHR) and stimulates CYP27B1 in the kidney leading to synthesis of 1α,25(OH)2D3. 1α,25(OH)2D3
inhibits its own production by: (i) inhibiting CYP27B1 in the kidney; (ii) inhibiting PTH secretion; and (iii)
stimulating FGF23 transcription in the bone. FGF23 binds to Klotho and the FGF receptor (FGFR) to inhibit
CYP27B1 providing a third negative feedback loop in the synthesis of 1α,25(OH)2D3. See text for more detailed
explanations. Broken lines with arrows indicate stimulation and solid lines indicate inhibition.
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FIGURE 13.4 Structure–function relationships and proposed mechanisms of gene induction and repression by
vitamin D receptor (VDR). (A) A schematic view of the functional domains in human VDR. (B) Allosteric model of
VDR–retinoid X receptor (RXR) activation after binding 1α,25(OH)2D3 and coactivator, phosphorylation and
docking on a high-affinity positive vitamin D response element (VDRE) (mouse osteopontin). See text for
explanation. (C) Allosteric model for VDR–RXR inactivation after binding 1α,25(OH)2D3 and corepressor,
dephosphorylation and docking in reverse polarity on a high affinity negative VDRE(chicken PTH). See text for
explanation. Source: reproduced with permission from Haussler et al. (2011) [3].
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FIGURE 13.5 The vitamin D receptor (VDR). (A) Organization of the VDR chromosomal gene. The human VDR
gene is located on chromosome 12q13-14 and spans approximately 60 kilobases of DNA. The gene is
composed of at least 5 noncoding exons and 8 coding exons. Alternative splicing results in at least 14 types of
transcripts. The translation start site (ATG) and termination (TGA) signals are shown in chapter 73. (B) Domains
A–Eare shown below the protein model. The DNA-binding domain consists of two zinc finger modules located at
the amino terminal portion of the receptor. The ligand-binding domain contains 12α-helices shown as open boxes
and 3β-turns shown as a filled box. The E1 and AF-2 subregions of the receptor are important in transactivation.
(C) A molecular model of the full retinoid X receptor (RXR)/VDR/deoxyribonucleic acid (DNA) complex. A stereo
representation of the cryo-electron microscopic (cryo-EM) map of the complex is fitted with the crystal structures
of individual RXR and VDR ligand-binding domains (LBDs) and DNA binding domain (DBDs), resulting in a
molecular model of the whole complex. The cryo-EM map is shown in magenta. The DNA is shown in blue with
the 5’ half-site of the response element in green and the 3’ half-site in red. The VDR DBD and LBD are shown in
orange and the RXR DBD and LBD shown in cyan. The ligands for VDR and RXR are shown in yellow and blue
van der Waals spheres. Helix 12 in the VDR LBD is shown in red. The VDR and RXR LBDs are oriented
perpendicular to the DNA and are anchored through the 5’ end of the response element. The hinges of both VDR
and RXR hold the complex in an open conformation to which coregulators can bind. Source: reproduced with
permission from Orlov et al. (2012) [6].
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FIGURE 13.6 Mutations in the vitamin D receptor (VDR) causing hereditary vitamin D resistant rickets (HVDRR).
A) depicts the two zinc finger modules and the amino acid composition of the deoxyribonucleic acid binding
domain (DBD). Conserved amino acids are depicted as shaded circles. Natural mutations are indicated by large
arrows. The location of the intron separating exon 2 and exon 3 which encode the separate zinc finger modules
is indicated by an arrow labeled intron. Numbers specify amino acid number. B) depicts the location of the αhelices (H1-H12) of the VDR LBD. The α-helices are depicted as filled boxes and the region containing the βturns is drawn as a cross-hatched box. The E1 and AF-2 regions are shown below the α-helices. The locations of
the mutations are indicated. Fs refers to a frameshift mutation.
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FIGURE 13.7 Mechanism of epithelial calcium transport. Paracellular calcium transport through tight junctions is
represented by the paracellular arrow. Transcellular calcium transport is carried out in three steps: (i) following
entry through the calcium channels TRPV5 and TRPV6, (ii) calcium will diffuse across the cell bound to
calbindin, and (iii) be extruded at the basolateral membrane via an adenosine triphosphate (ATP)-dependent
Ca2+-ATP-ase (PMCA1b) and Na+/Ca2+ (NCX1) exchanger mechanism. 1,25(OH)2D increases the expression of
calcium channels, calbindins, and the extrusion systems (arrows). Source: reproduced with permission from
Bindels (2005) [302].
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FIGURE 13.8 Immune modulatory effects of vitamin D3. Vitamin D3 is acquired via diet or synthesized in the skin
upon ultraviolet (UV) exposure. Cells of the immune system possess enzymes (CYP27A1, CYP27B1) to perform
the two hydroxylation steps needed to generate bioactive 1,25(OH)2D3. Next, 1,25(OH)2D3 binds to the VDR to
induce a range of immune modulatory effects. Source: reproduced with permission from Van Belle et al. (2011)
[398].
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FIGURE 13.9 The pathophysiologic pathways from vitamin D deficiency to osteoporosis, osteomalacia, falls, and
fracture. Source: reproduced with permission from Lips and van Schoor (2011) [409].
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