Is there more to learn about functional vitamin D metabolism?

Presented by Nabiilah Naraino Majie and Svenia Joorawon

Date: 26.01.2016

Table of content

• Introduction• Enzymes involved in functional metabolism

pathway• Vitamin D receptor (VDR)• Role of vitamin D in immune system• Conclusion• References

Introduction• Vitamin D is a fat-soluble vitamin which has an essential role in the body.

It is metabolised to its biologically active forms to carry out its functions.• In 1968, a more polar vitamin D was determined to achieve its functions

after handling unlabeled vitamin D or low-specific activity radioactive vitamin D.

• The discovered vitamin D was the 1st active metabolite of vitamin D isolated and identified and it is more potent than vitamin D3 since it promotes intestinal Ca transport and treats rickets.

• Chemical synthesis of the compound and addition of tritium in the molecule developed a more polar metabolite which was isolated in 1970 and its structure was identified as 1,25-(OH)2D3.

Introduction• Synthesised primarily in the kidneys, 1,25-(OH)2D3 is the metabolically

active form of vitamin D involved in intestinal Ca transport, bone Ca mobilisation and mineralisation of skeleton.

• In 1974, vitamin D endocrine system was detected through the deep research of the manufacture of 1,25-(OH)2D3. Besides, studies showed that a nuclear protein is the source of the vitamin D receptor (VDR).

• Isolation and investigations of VDR were performed by molecular cloning and meanwhile other metabolites of vitamin D were found namely 24,25-(OH)2D3 whose functions were vainly proved.

• Although several pathways of vitamin D have been now determined regarding the degradation and elimination of vitamin D compounds, other metabolism functions of vitamin D are still searched.

Enzymes involved in functional metabolism pathway

• Since any additional functional pathways of vitamin D have yet been discovered, the enzymes implicated in the activation of more polar vitamin D are defined.

• According to experiments performed on mice, the cloned enzyme CYP27B1 was indicated to be involved in the formation of 1,25-(OH)2D3 in the kidneys or other autocrine or paracrine tissues.

• This enzyme helps vitamin D in metabolism of Ca and phosphorus and skeleton and its activation is important in the treatment of rickets and osteomalacia.

• However, the initial step of its activation is unclear as animal studies have shown that only 75% of 1,25-(OH)2D3 is produced through CYP27B1 enzyme. So, the remaining 25% is still unidentified.

Vitamin D receptor (VDR)• VDR is located in many other tissues than in expected target tissues

responsible for:– Calcium homeostasis– Healing of rickets– Osteomalacia

• Vit D functions beyond skeletal health and growth• Selective anti-receptors have been defined that can yield many information

on tissue location.– Exclude tissues with VDR previously studied– Skeletal and heart muscles lack VDR– VDR found in keratinocytes, lymphocytes, macrophages etc

• In vitro studies showed that VDR may have non-genomic-related functions.

Role of vitamin D in immune system• Despite numerous studies, there is no association how VDR functions in

the immune system.• Vit D deficiency and excess play important role in immunosuppression.

– Vit D deficiency delays hypersensitivity– Vit D excess suppresses delayed hypersensitivity response

• Multiple sclerosis (MS) 1/Sunlight– UV7-dehydrocholesterolprevitamin DVit D3

– Is UV or Vit D responsible for suppression of MS?– Cantorna et al: Active Vit D suppressed Encephalomyelitis (EAE) but provoked

hypercalcemia (HC)– Low doses of Vit D that do not produce HC, do not suppress EAE. – Hypercalcemia not found when subject is exposed to UV

– Use of active Vit D cannot be used to treat MS or any autoimmune diseases.– Cantorna et al: Animals given low calcium diet along with Vit D lost its ability to

suppress EAE until high doses (causing HC) were given– Meehan et al: In females, HC itself could treat EAE but not MS while UV could treat

both without HC UV can treat these conditions within a narrow wave band of light (305-315nm) irrespective of Vit D

– Yang et al: In respect to hypersensitivity studies; showed that Vit D deficiency and absence of VDR can suppress or reduce EAE in mice.

– Thus, autoimmune diseases need the presence of Vit D and VDR.– Was it Vit D hormone or its precursor 25-hydroxy Vit D3?– Exp: CYP2R1& CYP27B1 were knocked-out could not prevent EAE– This suggests either there is some other form of Vit D which has still not been identified

or Vit D-receptor interaction is required for development of EAE.

Role of vitamin D in immune system

Conclusion• Vit D3 or an unknown metabolite is responsible for the development

of any component in the immune system.– Development of EAE– Any autoimmune diseases

• Vit D (poor ligand to VDR) & VDR are both required for EAE a metabolite is required

• Since it’s not the known metabolites; NOT ALL IS KNOWN ABOUT THE FUNCTIONAL

METABOLISM OF VITAMIN D

References• DELUCA, H.F., 2014. Is there more to learn about functional vitamin

D metabolism? Journal of Steroid Biochemistry & Molecular Biology; 148(2015), 3-6.