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a Department
of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Granada, Spain;
b Institute
of Nutrition and Food Technology “José Mataix,” Biomedical Research Center, University of Granada,
Granada, Spain; c Instituto de Investigación Biosanitaria ibs GRANADA, Complejo Hospitalario Universitario de
Granada, Granada, Spain; d CIBEROBN (CIBER Physiopathology of Obesity and Nutrition CB12/03/30028), Instituto de
Salud Carlos III, Madrid, Spain; e Thematic Networks of Cooperative Research-RETIC-, Carlos III Health Institute-ISCIII,
Keywords that act as transcription factors into the target cells after
Vitamin D · Calcitriol · Calcium · Novel actions forming a heterodimer with the retinoid X receptor. This kind
of receptors has been found in virtually all cell types, which
may explain its multiple actions on different tissues. Key
Abstract Messages: In addition to classic actions related to mineral
Background: Classically, vitamin D has been implicated in homeostasis, vitamin D has novel actions in cell proliferation
bone health by promoting calcium absorption in the gut and and differentiation, regulation of the innate and adaptative
maintenance of serum calcium and phosphate concentra- immune systems, preventive effects on cardiovascular and
tions, as well as by its action on bone growth and reorganiza- neurodegenerative diseases, and even antiaging effects.
tion through the action of osteoblasts and osteoclasts cells. © 2018 S. Karger AG, Basel
However, in the last 2 decades, novel actions of vitamin D
have been discovered. The present report summarizes both
classic and novel actions of vitamin D. Summary: 1,25(OH)2 Introduction
vitamin D, the active metabolite of vitamin D, also known as
calcitriol, regulates not only calcium and phosphate homeo- Vitamin D was first characterized like a vitamin in the
stasis but also cell proliferation and differentiation, and has 20th century and now it is recognized as a prohormone.
a key a role to play in the responses of the immune and ner- Two major forms of vitamin D are vitamin D2 (ergocal-
vous systems. Current effects of vitamin D include xenobi- ciferol) and vitamin D3 (cholecalciferol). Vitamin D3 is
otic detoxification, oxidative stress reduction, neuroprotec- synthesized in the skin of humans and is consumed in the
tive functions, antimicrobial defense, immunoregulation, diet via the intake of animal-based foods, mainly fish oils,
anti-inflammatory/anticancer actions, and cardiovascular
benefits. The mechanism of action of calcitriol is mediated
by the vitamin D receptor, a subfamily of nuclear receptors Presented at the IUNS Conference, Buenos Aires 2017.
HO HO
Vitamin D2 Vitamin D3
Skin
Photobiogenesis of vitamin D CH3
CH3 CH3
CH3
CH2
UV light 208–310 nm
HO
Vitamin D3
CH3 CH3
CH3
H CH3
H
CH3
H H H Previtamin D3
HO HO 5.9%
Liver
7-Dehydrocholesterol Previtamin D3
25(OH)D3
Vitamin D3
94.1%
HO Vitamin D3
Kidney
1,25-(OH)2 D3
whereas vitamin D2 is derived from plant sources, is not lease, which initiate emulsification and support the for-
largely human-made, and added to foods [1]. Vitamins mation of lipid-containing micelles, which diffuse into
D2 and D3 forms differ only in their side chain structure enterocytes [3]. Once absorbed, exogenous vitamin D is
(Fig. 1). The differences do not affect metabolism (i.e., packaged into chylomicrons, and thus is transported to
activation), and both forms have the prohormone func- the liver. A fraction of the vitamin D contained in the chy-
tion. lomicron can be taken up by adipose tissue and skeletal
muscle [4]. Once remnant chylomicrons reach the liver,
a specific carrier protein, the vitamin D binding protein
Vitamin D Absorption and Photobiogenesis (DBP) makes it possible for them to enter the hepatocytes
and later facilitates their transport to different tissues that
Vitamin D obtained from sun exposure, food, and need them. Endogenously, vitamin D3 can be photosyn-
supplements is biologically inactive (either the vitamin thesized in the skin.
D2 or D3) and must undergo activation through 2 con- 7-Dehydrocholesterol (provitamin D3) is converted to
secutive enzymatic hydroxylation reactions occurring in the previtamin D3 form (precalciferol) following its expo-
the liver and kidney (Fig. 1). sure to ultraviolet B (UVB) radiation [1]. Subsequently, it
Dietary vitamin D (either vitamin D2 or D3) is usually can suffer a thermal isomerization to vitamin D3 in the
absorbed at the small intestine with other dietary fats [2]. epidermis (Fig. 1). Alternatively, previtamin D3 may be
The presence of fats in the lumen triggers bile acids re- photoconverted to nonactive forms, such as tachysterol
+ + + + +
Osteoblast Mineralization Osteoblast Osteoblast
Differentiation/ Ca2+ binding
differentiation activation differentiation
mineralization of
growth plates Osteoblast
Primary Growth
chondrocytes Non-mineralized factors Osteoblast
matrix cytokines precursors
Hypertrophied
chondrocytes Osteocalcin/osteobindin
Calcified Osteoblast
Osteocytes
chondrocytes cells
Primary
esponge Bone
absorption that depends on its presence in the diet, intes- secretion of the receptor activator for nuclear factor kap-
tinal solubility, and intestinal absorption capacity, which pa-B ligand, which, in turn, is responsible for osteoclas-
is the result of the balance between transcellular and para- togenesis and bone resorption [20]. At the same time, vi-
cellular intestinal absorption [2]. When calcium intake is tamin D inhibits mineralization through the increase of
high, paracellular transport will be sufficient [17]. Trans- pyrophosphate levels and osteopontin [21]. Calcitriol
cellular transport involves 3 phases: (1) entrance of cal- promotes bone formation and growth, by activating
cium through specific calcium channels (such as TRPV6) chondrocyte differentiation, and increasing serum calci-
present in membranes of the brush border; (2) intracel- um and phosphate levels. Thus, vitamin D deficiency re-
lular transport mediated by calbindin; and (3) calcium sults in inadequate mineralization of the skeleton, and
active transport to the blood stream at the basolateral sur- when low vitamin D levels are maintained, bone growth
face mainly mediated by specific carriers [2, 14, 17]. plates cannot be mineralized due to calcium and phos-
The second organ are the kidneys; calcitriol with PTH phate depletion [22, 23].
encourages the renal distal tubule reabsorption of calci-
um. Calcitriol influences (1) calcium entrance through
the apical membrane; (2) calbamicin-mediated calcium Mechanisms of Action of Vitamin D
diffusion; and (3) active transport thought the basolateral
membrane [18]. Vitamin D inhibits phosphate reabsorp- The mechanism of action of the calcitriol is mediated
tion indirectly by increasing FGF-23 osteocytes expres- by the VDR, which belongs to a subfamily of nuclear re-
sion, and directly by inducing α-klotho (FGF-23 co-re- ceptors that act as transcription factors into the target
ceptor) [14]. cells after forming a heterodimer with retinoid X receptor
The third target tissue is the bone. Calcitriol mobilizes (RXR). Once dimerized, the complex binds to the VDR
calcium from bone, a process requiring PTH [19]. When element, in the promoter regions of target genes or at dis-
serum calcium levels decrease, PTH-dependent calcitriol tant sites, to positively or negatively regulate their expres-
activation prompts the formation and VDR-mediated sion [24]. As the VDR has been found in virtually all cell
differentiation of osteoclasts. This activation induces the types [25], it may explain its multiple actions on different
mobilization of calcium from the bone by stimulating the tissues [26].
Diffusion
VDRnuc 1,25
Corepressor
Receptor RxR VDR
binding
Promoter
+ VD3 - Corepressor
AR Dimerization + Coactivator
RXR
Coactivator
VD3
Transcription PCAF CBP/p300 SRCs Ac Ac
regulation RxR VDR
Pol II
VDRE Promoter
5’-GGGTCA-NNN-GGTCA-3’
Ac
Fig. 3. Molecular mechanism of action of vitamin D. CBP/p300; CREB-binding protein binding protein p300,
PCAF; P300/CBP-associated factor, SRC, steroid receptor coactivators.
Besides 1,25(OH)2D3, the VDR-RXR dimer can asso- human antimicrobial peptide cathelicidin in lung epithe-
ciate with other molecules as the p160 coactivators fam- lial cells, and Runx2 and VDR collaborate in the tran-
ily of steroid receptor coactivators 1, 2, and 3, that have scriptional regulation of mouse osteopontin in osteoblas-
histone acetylase (HAT) activity, and are primary coacti- tic cells [30]. C/EBP, Runx2, and VDR all contribute to
vators that bind to the AF2 domain of liganded VDR [27]. the control of matrix metalloproteinase 13 gene tran-
Members of p160 family recruit proteins as secondary co- scription [31]. The SWI/SNF complexes contribute to
activators, such as CBP/p300, which also have HAT activ- transcriptional activation by VDR. C/EBP recruits the
ity, resulting in a multi-subunit complex that modifies SWI/SNF complex to promote 1,25(OH)2D3 induction of
chromatin and destabilizes histone/DNA interaction Cyp24a1 and Bglap transcription [32] (Fig. 3).
[28]. The modification of histones occurs not only by Low-affinity nutritional VDR ligands including cur-
acetylation, but also through methylation [27]. Liganded cumin, polyunsaturated fatty acids, and anthocyanidins
VDR interacts with basal transcription factors (TFIIB and initiate VDR signaling, whereas the longevity factors res-
several TATA DNA box binding protein-associated fac- veratrol and sirtuin 1 potentiate VDR signaling [33]. The
tors). VDR-intermediated transcription is facilitated by result of VDR genomic interactions is the transcription
the mediator, a multi-protein complex that functions regulation of multiple genes, in many cases far from the
through the recruitment of RNA polymerase II and pro- cis site of VDR binding. However, in a few cases, VDR can
motes the formation of the preinitiation complex [29] exert a regulatory action in the absence of calcitriol.
(Fig. 3). The overarching principles of 1,25(OH)2D3-mediated
There is increasing evidence that specific CAAT en- gene regulation in target cells are as follows: i) VDR-
hance binding protein (C/EBP) family members may be binding sites are about 2,000–8,000; ii) active transcrip-
key mediators of 1,25(OH)2D3 action. C/EBP is induced tion unit is the VDR/RXR heterodimer; iii) distal-bind-
by 1,25(OH)2D3 in kidney and osteoblastic cells and co- ing site location is dispersed in cis-regulatory modules
operates with 1,25(OH)2D3 and VDR in enhancing (enhancers) across the genome; iv) VDR/RXR-binding
Cyp24a1 and Bglap genes transcription [30]. C/EBP and site sequence (VDR element) is mediated by classic hex-
VDR cooperate in the transcriptional regulation of the americ half-sites (AGGTCA) separated by 3 base pairs
TH
Suppression of TH TREG
CYP2761 Calcitriol Lipopeptide
Inflammation and H OH
TH17 TLR
autoimmunity H
VDR
H
CYP27B1
TH1 cytokines and Calcidiol +
Bcell TH2 HO
immunoglobulins
HO
Tcell +
TH1 TH1
Tcell
TH1 cytokines TH2
DC TH17
–
Macrophage or keratinocyte
TL
R Cathelicidin
CD4 Innate immunity
MØ differentiation TLR
TREG
Cytokines
Bacterial killing
e Antigen presentation
Macrophag
Monocyte
DC maduration
Path
ogen Innate immunity
Fig. 4. Vitamin D effects on innate and adaptative immunity. CYP, cytochrome; MØ, macrophage; TH, T-helper
cell; TLR, toll-like receptor; TREG, T regulatory cell, VDR, vitamin D receptor.
Vitamin D and the Immune System Regulation of the Innate Immune Response by DC and
Macrophages
1,25(OH)2D3 has important immunomodulatory ac- Calcitriol increases the defense capacity of macro-
tions, namely, the enhancement of the innate immune phages inducing their differentiation, phagocytic capac-
system and inhibition of the adaptative immune respons- ity, and antimicrobial activity (increasing the expression
es, associated with an increased synthesis of interleukin of cathelicidins). Moreover, calcitriol inhibits the prolif-
(IL)-4 by T helper (Th)-2 lymphocytes and the upregula- eration of monocytes, and promotes the differentiation of
tion of regulatory T lymphocytes (T-reg). In fact, differ- monocytes to macrophages, these effects being mediated
ent types of immune cells, for example, dendritic cells by the upregulation of Fc surface cell receptors and by an
(DC), macrophages, and T and B lymphocytes express increase in cell respiration. In addition, calcitriol inhibits
VDR and most of them are able to synthesize calcitriol DC proliferation, maturation, as well as their immuno-
through an independent regulation pathway responding stimulatory properties leading to the induction of T-reg
to a number of proinflammatory agents as bacterial lipo- cells. Consequently, vitamin D deficiency results in a less
polysaccharide and tumor necrosis factor alpha (TNF-α) tolerogenic status to foreign antigens [26, 27].
[24].
Macrophages-derived cytokines promote Th differ- Inhibition of the Pro-Inflammatory Response of APC
entiation to Th0 cells. Later, with the cooperation Calcitriol inhibits the expression of APC cytokines,
of some costimulatory exogenous cytokines produced namely, IL-1, IL-6, IL-12, and TNF-α and decreases the
by a number of antigen presenting cells (APC), name- expression of a set of major histocompatibility complex
ly, macrophages and DC, Th0 differentiate to Th1 or class II cell surface proteins in macrophages, and the de-
Th2 cells, which in turn regulates cell and antibody velopment of proinflammatory Th1 and Th17 cells, while
immune responses. Calcitriol can regulate the im-
inducing T-reg and Th2 cells, which in turn downregulate
mune responses in secondary lymphoid organs as well the activity of Th1. Thus, calcitriol inhibits the produc-
as in target organs through a number of mechanisms tion of IL-12 and stimulates the production of IL-10,
(Fig. 4). while downregulating the expression of some costimula-