CHAPTER 10 The Fat-Soluble Vitamins 385

Retinoic acid also may be able to modify cell surfaces,

possibly by increasing glycoprotein synthesis at the gene
level or by improving the attachment of glycoproteins to
cell surfaces to induce cell adhesion [18]. Retinol may also
play a more direct role in glycoprotein synthesis. Retinyl
phosphate (generated from retinol plus ATP) can be con-
verted to retinyl phosphomannose (also called mannosyl
retinyl phosphate) in the presence of GDPmannose. Reti-
nyl phosphomannose can in turn transfer the mannose
to glycoprotein acceptors. On receipt of the mannose, the
glycoprotein acceptors become mannosylated glycopro-
teins [18]. Such changes in the glycan portion of the glyco-
protein can greatly affect differentiation of cells or tissues
through their effects on cell recognition, adhesion, and cell
aggregation. These reactions involving vitamin A and gly-
cosylation are shown here.
Retinyl
phosphomannose
GDP
Retinyl
phosphate
Glycoprotein
acceptor
Mannosylated
glycoprotein
GDP
mannose
Other Functions Vitamin A, as retinol but not as retinoic
acid, is essential for reproductive processes in both males
and females, although the mechanism(s) of its action(s)
are unclear [20]. Bone development and maintenance
also require vitamin A. Vitamin A is necessary for bone
metabolism through involvement with osteoblasts (bone-
forming cells) and osteoclasts (cells involved in bone
resorption). Although the mechanism of action is unclear,
vitamin A deficiency results in excessive deposition of
bone by osteoblasts and reduced bone degradation by
osteoclasts. Excess vitamin A, in contrast, stimulates osteo-
clasts and inhibits osteoblasts, decreasing bone mineral
density and increasing fracture risk. Vitamin A appears to
be involved in hematopoiesis and iron distribution among
tissues, also by an unknown mechanism of action. Several
aspects of immune system function, both humoral and cell-
mediated, also are influenced by vitamin A. Retinoic acid,
for example, stimulates phagocytic activity and cytokine
production and maintains natural killer cell concen-
trations [21]. Depletion studies suggest that vitamin A
appears to be needed for T-lymphocyte function and for
antibody response to viral, parasitic, and bacterial infec-
tions [21]. Thus, people with vitamin A deficiency have an
impaired ability to resist and fight infections. Another role
of vitamin A, likely mediated by effects on gene expression,
and cell differentiation and growth, is in morphogenesis/
embryogenesis. Specifically, retinoic acid is thought to act
as a morphogen in embryonic developments, and nuclear
Retinoic acid response elements (RARE)
Cytosol
DNA
Nucleus
, , or
retinoid X receptors
(RXR)
9-cis retinoic
acid
, , or
retinoic acid
receptors (RAR)
All-trans
retinoic acid
Changes
in
protein
synthesis
Changes
in mRNA
transcription
R
A
R
Dimer
Coactivator
R
X
R
Retinoic acid
receptor
Corepressor
Corepressor
9-cis retinoic
acid
All-trans
retinoic acid
CRABP CRABP
Release of the receptor from the
corepressor allows the vitamin to bind
to the receptor.

All-trans or 9-cis retinoic acid moves into the nucleus of the cell.
All-trans retinoic acid binds to retinoic acid receptors (RAR) and 9-cis retinoic acid binds to retinoid X receptors (RXR). These vitamin-bound
receptors attach to specifc sites on the DNA referred to as retinoic acid response elements (RARE), found in the promoter region of specifc
genes.
Binding of the receptors to RARE on the DNA enhances the transcription of selected genes.

Figure . Hypothesized mode of action for retinoic acid on gene expression.