Metabolic functions of vitamin D

Metabolic functions of
vitamin D
Domina Petric, MD

• Vitamin D3 has specific cells in target organs
with specific receptor proteins.
• The receptor–ligand complex moves to the
nucleus, where it binds to the chromatin at
specific DNA sequences and stimulates the
transcription of certain downstream genes to
produce specific mRNAs that encode the
synthesis of specific proteins.
April 9, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
Vitamin D3 as a steroid hormone

The clearest physiological role of
vitamin D is in the maintenance of
calcium and phosphate
homeostasis, impairment of which
produces the lesions in bone called
rickets and osteomalacia.
April 9, 2018
1,25-(OH)2-D3 as the metabolically
active form

April 9, 2018
Roles of vitamin D in calcium and
phosphorus metabolism

• Calcium is absorbed in the small intestine by both
transcellular and paracellular mechanisms.
• The active metabolite (1,25-(OH)2-D3)
stimulates the enteric absorption of calcium
through roles in both mechanisms.
• The availability of calcium for both processes is
affected by both exogenous (inhibition by food
phytates or phosphate) and endogenous (gastric
acid secretion) factors.
April 9, 2018
Intestinal absorption of Ca2+

The transcellular process of enteric calcium absorption
has three components, each of which is stimulated by
1,25-(OH)2-D3:
• Uptake of Ca2+ from the intestinal lumen to the
microvillus border.
• Translocation of Ca2+ across the cell to the
basolateral membrane.
• Active extrusion of Ca2+ into the circulation.
April 9, 2018

• The paracellular process of calcium
absorption is stimulated by 1,25-(OH)2-D3.
• Vitamin D can affect the diffusional
permeability of tight junction complexes
to calcium, possibly by 1,25-(OH)2-D3-
mediated second messengers.
April 9, 2018

• Vitamin D increases the mucosal uptake of
phosphorus and enhances its absorption from the
lumen of the gut.
• The active metabolite 1,25-(OH)2-D3 appears
to modulate the number of carrier sites available
at the mucosal membrane for a sodium-dependent
phosphate entry.
• At least in the duodenum, this process is
independent of calcium absorption.
April 9, 2018
Intestinal phosphate absorption

• Vitamin D, as 1,25-(OH)2-D3, stimulates the
resorption of both phosphate and Ca2+ in the
distal renal tubule.
• The quantitative significance of this effect
is greater for phosphate than it is for Ca2+.
• Most of the calcium (80%) is resorbed by
passive, vitamin D-independent, paracellular
routes in the proximal tubules and ascending
loop of Henle.
April 9, 2018
Renal resorption of calcium and
phosphate

The transcellular process resembles
that of the intestine in having a Ca2+
channel component, cytosolic Ca2+
binding proteins (calbindin-D28k) and a
plasma membrane Ca2+ ATPase, all of
which are expressed in 1,25-(OH)2-D3-
responsive nephrons.
April 9, 2018
Renal resorption of calcium and
phosphate

• Bone is the largest target organ for vitamin D.
• Bone contains mainly 25-OH-D3, accounting
for >50% of the vitamin D metabolites
present, with 1,25-(OH)2-D3 comprising less
than 35%.
• As in plasma, the level of 24,25-(OH)2-D3 in
bone is fairly constant relative to that of
25-OH-D3.
April 9, 2018
Bone mineral turnover

Vitamin D plays roles in both the formation
(mineralization) of bone and in the mobilization
of bone mineral (demineralization).
Vitamin D stimulates osteoclast-mediated bone
resorption.
Vitamin D has a role in the differentiation of
macrophages to osteoclasts.
April 9, 2018

• The demineralization of bone serves to mobilize
Ca2+ and phosphate from that reserve.
• The process of bone resorption involves
PTH, which appears to act via cAMP (PTH
stimulates adenylcyclase activity) in a mechanism
involving a 1,25-(OH)2-D3-dependent factor.
• Because PTH is secreted in response to
hypophosphatemia, nutritional deprivation of
phosphate can lead to bone demineralization.
April 9, 2018

• The normal concentration of Ca2+ in the serum of most
species is about 10 mg/dl.
The vitamin D dependent homeostatic system responds to
perturbations of that level by modulating Ca2+ entry to
and exit from the plasma via three portals:
• intestine
• kidney
• bone
April 9, 2018
Calcium and phosphate homeostasis

• When the serum Ca2+ concentration falls
below this target level (hypocalcemia), PTH
is secreted by the parathyroid glands, which
function to detect hypocalcemia.
The kidney responds to PTH in two ways:
• phosphate diuresis
• stimulation of 25-OH-vitamin D 1-hydroxylase
April 9, 2018

• Stimulation of 25-OH-vitamin D 1-hydroxylase
increases the production of 1,25-(OH)2-D3, which
acts (by inducing calbindin) in the intestine to
increase the enteric absorption of both Ca2+ and
phosphate.
• 1,25-(OH)2-D3 acts jointly with PTH in bone to
promote the mobilization of Ca2+ and phosphate.
• The aggregate result of these responses is to
increase the concentrations of Ca2+ and phosphate
in the plasma.
April 9, 2018

• Under conditions of increased
circulating concentrations of Ca2+
(hypercalcemia), calcitonin (CT) is
secreted by the thyroid gland (C cells).
• CT suppresses bone mobilization and
increases the renal excretion of both
Ca2+ and phosphate.
April 9, 2018

The 25-OH-vitamin D 1-
hydroxylase may be feedback
inhibited by 1,25-(OH)2-D3, and
may actually be converted to the
catalysis of the 24-hydroxylation
of 25-OH-D3.
April 9, 2018

• Calcium deposition in the skeleton involves the
intracellular synthesis of collagen and fibrils by
the bone-forming osteoblasts, which extrude
these fibrils to form the extracellular matrix of
bone, portions of which can be mineralized.
• Calcium mobilization from bone is directed by
multinucleated osteoclasts that release
proteins and lysosomal enzymes that dissolve
bone mineral and lyse its organic matrix.
April 9, 2018

April 9, 2018

April 9, 2018
Vitamin D function can be affected by several other
mineral elements...

Deprivation of zinc has been found to
diminish the 1,25-(OH)2-D3 response
to low calcium intake.
Zinc may indirectly affect renal
25-OH-D3 1-hydroxylase activity.
April 9, 2018
Zinc

• Iron deficiency has been shown to be
associated with low serum concentrations of
24,25-(OH)2-D3 and reduced 25-OH-D3
responses to supplementation with vitamin D3.
• Iron deficiency impairs the enteric absorption
of fat and vitamin A.
• It may also impair the absorption of vitamin D.
April 9, 2018
Iron

Exposure to lead also
appears to impair the
1-hydroxylation of
25-OH-D3.
April 9, 2018
Lead

April 9, 2018
Vitamin D functions in noncalcified
tissues

Effects of 1,25-(OH)2-D3 are:
• inhibition of immunoglobulin secretion by B
lymphocytes
• inhibition of production of interleukins 2 (IL-2)
and 12 (IL-12), IL-2 receptor (IL-2R), granulocyte
macrophage colony-stimulating factor and
interferon-γ by T cells
• inhibition of accessory cell and antigen-
presenting cell activities
April 9, 2018
Role of vitamin D in immune function

1,25-(OH)2-D3 has
been found to
enhance macrophage
and monocyte
phagocytosis,
bacterial killing and
heat shock protein
production.
April 9, 2018
Role of vitamin D in immune function

• Vitamin D deficiency reduces the
secretion of insulin.
• Subclinical, low-intensity, chronic
inflammation has been associated with
insulin resistance, which has been found
to be inversely related to serum
25-OH-D3 concentrations over a wide
range.
April 9, 2018
Vitamin D and noninsulin-dependent
diabetes

• The relationship of vitamin D status and NIDDM
risk appears to be greatest among
overweight/obese individuals.
• Serum 25-OH-D3 levels are inversely correlated
with body mass index and body fat mass.
• Low vitamin D status as a risk factor for NIDDM.
• This effect can be exacerbated by adiposity due to
the removal of the vitamin from functional pools
as a result of its partitioning into bulk lipid depots
in adipose tissue.
April 9, 2018
Vitamin D and noninsulin-dependent
diabetes (NIDDM)

Type I diabetes mellitus
Multiple sclerosis
Rheumatoid arthritis
Irritable bowel disease
Crohn´s disease
April 9, 2018
Vitamin D and autoimmune diseases

Circulating concentrations of
25-OH-D3 have been found
to be inversely correlated
with the risk of periodontal
disease in adults.
April 9, 2018
Vitamin D and periodontal disease

• Low vitamin D status may be a risk factor for
cerebrovascular diseases.
Vitamin D is known to suppress several
mechanisms of CVD pathogenesis:
• proliferation of vascular smooth muscle
• vascular calcification
• production of pro-inflammatory cytokines
• regulation of the renin-angiotensin system
April 9, 2018
Vitamin D and cardiovascular disease

April 9, 2018
Vitamin D and proliferative skin
diseases
Both oral and topical
applications of appropriate
doses of either 1,25-(OH)2-D3 or
the synthetic analog 1α,25-
(OH)2-D387 can be safe and
effective in the management of
psoriasis.

Vitamin D plays an important role in muscle.
Muscular weakness and hypotonia are seen in rickets.
Patients with osteomalacia frequently show myopathy.
Insufficient vitamin D status may increase the risk to
bone fracture by affecting strength, balance and gait.
April 9, 2018
Vitamin D and muscular function

Vitamin D may be protective against colon cancer.
Low serum 1,25-(OH)2-D3 levels may be associated with
increased risk of breast cancer.
1,25-(OH)2-D3 can inhibit cell proliferation, induce cell
differentiation and induce apoptosis.
Physiological concentrations of 25-OH-D3 inhibit
mammary cells, which can also produce 1,25-(OH)2-D3.
April 9, 2018
Vitamin D and cancer

1,25-(OH)2-D3 has been
found to suppress cell division
and induce differentiation by
downregulating expression of
the protooncogene c-myc.
April 9, 2018
Vitamin D and cancer

April 9, 2018
Parathyroid gland

The parathyroid gland has a central role in
the physiological function of vitamin D.
The gland senses serum calcium levels.
When calcium levels drop, it increases
secretion of PTH into the circulation.
Parathyroid hormone (PTH) is essential to
vitamin D function.
April 9, 2018
Central role of the parathyroid gland
in facilitating vitamin D function

• Increasing serum PTH levels stimulate the
renal 25-OH-D3 1-hydroxylase, thus
increasing the production of 1,25-(OH)2-D3.
• PTH facilitates the stimulation by 1,25-
(OH)2-D3 of both osteoclastic activity and
renal calcium resorption, both of which
activities serve to restore the plasma Ca2+
concentration.
April 9, 2018

Secondary hyperparathyroidism, characterized
by elevated serum PTH concentrations, is
common among elderly people.
The condition can reflect some degree of renal
insufficiency, with associated reduction in
renal 25-OH-vitamin D3 1-hydroxylase activity.
April 9, 2018

The most advantageous serum
25-OH-D3 concentration are
90-100 nmol/L (36–40 ng/ml).
Such levels require regular
daily vitamin D intakes of
greater than 1000 IU (40 mcg).
April 9, 2018
Healthful intakes of vitamin D

• Combs GF. The Vitamins. Fundamental Aspects
Literature
April 9, 2018

Metabolic functions of vitamin D

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