KINESIOL 1Y03 Chapter Notes - Chapter 11: Retinoid X Receptor, Brush Border, Corepressor
22 Jun 2018
School
Department
Course
Professor
Calcium, Vitamin D and osteoporosis (Julian Walters)
Normal calcium physiology
•1kg in adults, 99% of which is in bone; 1% or 1gram of which is in blood
•has crucial roles in intracellular signaling
•300-1300g per day = normal dietary intake; much of this passes through the kidneys;
most is re-absorbed, 150g is lost
•small amount secreted in GI fluids (100-150g)
•25g lost through the skin
•more calcium needed in childhood and adolescence to reach peak bone mass,
pregnancy and lactation to support infant needs and post-menopause and elderly to
compensate for trend in loss of bone minerals.
•During pregnancy 30g is lost to the foetus and 260g lost in milk/day hence 500-
1000g required to be taken in in supplements
Calcium absorption
Affected by:
1) diet – differs across foods; differing availability from foods e.g. liquid supplement
c/f/ chewing on bone; solubility in gastric acid v.important
2) absorption in duodenum and proximal jejunum – transit time; specific genes
expressed
3) regulation by vitamin D in the hormonal system
Vitamin D
•Has classical roles in intestine, kidney and bone
•Also has immune functions: expressed in macrophages, monocytes, dendritic cells
(important in granuloma formation in sarcoid/TB) as well as lymphocytes (implicated
in immune disorders e.g. IBD, MS, DM)
•May have a role in proliferation/cancer prevention e.g. in psoriasis, CRC, breast
cancer
•Deficiency due to lack of sunlight causes rickets in children and osteomalacia in
adults
•These are “lack of bone calcification” due to lack of vitamin D
•Insufficient energy in light and decreased exposure to light in winter months hence
blood levels fall sept-march; 500IU of vit D and 500mg Ca supplements can replace
this.
Vitamin D synthesis:
•1) 7-decholesterol in skin sunlight pro-vitamin D3 vitamin D3 vitamin D
•1) dietary sources = Vitamin D3 or vitamin D2 vitamin D
•2) vitamin D in circulation liver hydroxylated by 25-hydroxlase to 25-hydroxyD3
= MAJOR STORAGE FORM
•3) 25-hydroxyD3 kidney hydroxylated by 1alpha-hydroxylase to 1,25-
dihydroxyD3 = ACTIVE
•4) BREAKDOWN of 1,25-dihydroxyvitD by 24-hydroxylase (expressed in vit D target
tissues) to: 1, 24, 25-trihydroxyvitD or 24, 25-dihydroxyvitD = INACTIVE
find more resources at oneclass.com
find more resources at oneclass.com
Vit D receptor (VDR)
•intracellular “steroid hormone” family receptor which dimerises with retinoid X
receptor (RXR) activating transcription of target genes which have Vitamin D
response elements (VDREs)
•CDR must be bound to 1,25-dihydroxyvitD and RXR must be bound to 9-cis retinoic
acid during dimerisation for activation
•There are 2 types of VDRE:
1) Direct Repeat spaced by 2 (DR3) = very strong:
consensus RGKTSA where R = purine i.e. A or G, K = keto i.e. G or T and S =
strong i.e. G or C
example: AGGTCA nnn AGGTCA
2) Inverted Palindrome spaced by 9 (IP9) = strength unknown:
example: TGACCT nnnnnnnnn AGGTCA
•Examples of genes with VDREs are: 25-hydroxylase, TRPV6, PTH, cathelicidin
Variables affecting VitD-dependant gene expression
1) VitD concentraion: plasma levels, local tissue production/metabolims e.g. can be
produced by macrophages, cellular uptake
2) VitD receptor: concentration, polymorphisms, differential splicing
3) Other ligands: bile acids
4) VDRE affinity
5) RXR/ other co-activators / co-repressors
Vit D and hypocalcaemia
•classical vit D deficiency causes decreased Ca
•however, calcium deficiency can vit D deficiency e.g. in malabsoprtion
This is because low calcium causes increased PTH increased renal hydroxylase increased
vitD increased 24-hydroxlase which breaks down active D3 increased catabolism of vit D
metabolites hence reduced stores
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
1kg in adults, 99% of which is in bone; 1% or 1gram of which is in blood has crucial roles in intracellular signaling. 300-1300g per day = normal dietary intake; much of this passes through the kidneys; most is re-absorbed, 150g is lost small amount secreted in gi fluids (100-150g) 25g lost through the skin: more calcium needed in childhood and adolescence to reach peak bone mass, pregnancy and lactation to support infant needs and post-menopause and elderly to compensate for trend in loss of bone minerals. During pregnancy 30g is lost to the foetus and 260g lost in milk/day hence 500- 1000g required to be taken in in supplements. Has classical roles in intestine, kidney and bone. Deficiency due to lack of sunlight causes rickets in children and osteomalacia in adults. These are lack of bone calcification due to lack of vitamin d.
