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Fellow Seminar

Fellow Seminar. Topic: Vitamin D: a pleiotropic hormone Comment ：洪振傑 醫師 報告人員： F2 張春偉 報告時間： 99-09-15. OUTLINE. VITAMIN D – NORMAL METABOLISM VITAMIN D IN BONE & CALCIUM HOMEOSTASIS VITAMIN D & CANCER VITAMIN D AS IMMUNE MODULATOR CARDIOVASCULAR & METABOLIC ACTIONS RENAL PROTECTION

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Fellow Seminar

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  1. Fellow Seminar • Topic: Vitamin D: a pleiotropic hormone Comment ：洪振傑 醫師 報告人員：F2 張春偉 報告時間：99-09-15

  2. OUTLINE • VITAMIN D – NORMAL METABOLISM • VITAMIN D IN BONE & CALCIUM HOMEOSTASIS • VITAMIN D & CANCER • VITAMIN D AS IMMUNE MODULATOR • CARDIOVASCULAR & METABOLIC ACTIONS • RENAL PROTECTION • CLINICAL PERSPECTIVES

  3. VITAMIN D - NORMAL METABOLISM

  4. In kidney, mitochondria of epithelial cells in the proximal nephron reabsorption of 25-hydroxyvitamin D + DBP from tubular fluid • By megalin-dependent mechanism • Calcitriol is then released into peritubular blood • Circulates in plasma again bound to DBP

  5. Vitamin D binding protein • DBP • ~ 58-kDa protein synthesized in the liver • Human serum levels: 4 - 8 μM • Half life: 3 days • The parent vitamin D, 25(OH)D, & 1,25(OH)2D are carried in the circulation by DBP • But the greatest affinity is for 25(OH)D

  6. Vitamin D binding protein • Primary role • Maintain stable serum stores of vitamin D metabolites & modulate the rates of bioavailability, activation, & end organ responsiveness • Deficiency of DBP • Occur in nephrotic syndrome due to urinary protein losses • Leading to low 25(OH)D serum levels

  7. Genomic mechanism • At the cellular level, receptor (megalin)–mediated endocytosis of both calcidiol & calcitriol • Inside the cell, 1,25(OH)2D • Inactivated by mitochondrial 24-hydroxylase • Or bind to the VDR in the cytoplasm • VDR-ligand binding occurred => VDR translocates to the nucleus • => Heterodimerizes with the retinoid X receptor

  8. Genomic mechanism • This complex binds the vitamin D response element of target genes • Recruits transcription factors & corepressors/activators that modulate the transcription • These corepressors & coactivators appear to be specific for the ligand • Different forms & analogs of vitamin D may produce different effects

  9. Nongenomic • Exert biologic effects over periods of time that are too short to be explained by genomic mechanisms • A discrete receptor, or membrane-associated protein • Distinct from the VDR may mediate these rapid nongenomic actions

  10. Transcaltachia • Increases in intestinal Ca transport within 10 - 15 minutes after adding 1,25-dihydroxyvitamin D to fluid used to perfuse the lumen of the proximal small intestine

  11. Impact of Chronic Kidney Disease on Vitamin D Metabolism • Cross-sectional studies • 1,25-dihydroxyvitamin D decrease progressively as renal function declines • Reductions in renal synthesis • Adversely affects intestinal Ca absorption => modest reductions in serum Ca concentration • => Hypocalciuria • Several mechanisms involved

  12. Consequences of Impaired Renal Calcitriol Synthesis in Chronic Kidney Disease • Calcitriol modulates the expression of several key proteins responsible for the transepithelial movement of Ca • Not only in intestine but also in kidney • Calbindins • Vitamin D-dependent proteins • Buffer free Ca within the cytoplasm of epithelial cells in Ca-transporting epithelia • Translocation of Ca from the apical to the basolateral cell membrane

  13. Calcitriol + Ca modulates the expression of 2 proteins • Vanilloid family of transient receptor potential (TRP) proteins • TRPV-5 & TRPV-6 • Constitutively activated Ca channel • Mediates Ca uptake across the apical membrane of renal & intestinal epithelial cells

  14. Extrarenal Calcitriol Synthesis • Other tissues also express the 25-hydroxyvitamin D-1-α-hydroxylase • => 1,25-dihydroxyvitamin D synthesis regulated in a tissue-specific manner • => serve as autocrine or paracrine

  15. VITAMIN D IN BONE & CALCIUM HOMEOSTASIS

  16. 1,25(OH)2D3 • Major calcitropic hormone • Keep the plasma Ca2+ within narrow limits • Renal production regulated by 2 hormones • PTH • Hypocalcemia => secretion of PTH by the parathyroid gland • PTH targets the kidney • Decrease Ca2+ excretion, inhibit phosphate reabsorption, & stimulate 1,25(OH)2D3 production

  17. FGF23 • 1,25(OH)2D3 stimulates the secretion of FGF23 by the osteocytes • Major phosphaturic hormone • Inhibiting renal phosphate reabsorption • By the specific transporter NaPiT2a • Decrease renal production of 1,25(OH)2D3

  18. Genetic deficiencies in 1,25(OH)2D3 • Loss of CYP27B1 or VDR • => hypocalcemia, hyperparathyroidism, hypophoshatemia, rickets, & osteomalacia • The phenotype can largely be corrected by administration of a high Ca diet • Bypasses 1,25(OH)2D3 -mediated, Ca2+ absorption - Endocr Rev 2008;29: 726–776

  19. Reintroducing VDR in the intestine of VDR null mice rescued the hypocalcemia & the bone phenotype - Gastroenterology 2009; 136:1317–1327 - J Bone Miner Res 2008; 23: S104 • The proteins involved in this active intestinal Ca2+ transport remain poorly defined.

  20. TRPV6, Calbindin • Main mediators of 1,25(OH)2D3 -induced intestinal Ca2+ absorption • Inactivation of TRPV6 & calbindin D9k not impair intestinal Ca2+ absorption when dietary Ca intake is normal • => compensatory proteins

  21. TRPV6 is critical for Ca2+ absorption when dietary Ca intake is low • Impaired intestinal Ca2t absorption in TRPV6 null mice on a low Ca diet - J Bone Miner Res 2007; 22: 274–285 - Endocrinology 2008; 149: 3196–3205

  22. Hypothesis: 1,25(OH)2D3 action not only affects transcellular but also paracellular Ca2+ transport • Regulate tight junction permeability in the intestine by modifying the expression of several tight junction proteins • Claudin-2 & claudin-12 - Mol Biol Cell 2008; 19: 1912–1921

  23. TRPV5 is definitely critical for renal Ca2+ reabsorption • TRPV5 null mice • Profound Ca2+ wasting • With compensatory increased intestinal Ca2+ absorption • Due to high 1,25(OH)2D3 serum levels, & normocalcemia as a result - J Clin Invest 2003; 112: 1906–1914

  24. Direct effect of 1,25(OH)2D3 on bone homeostasis? • 1,25(OH)2D3 stimulate bone resorption • Increasing the expression of osteoclastogenic factors in osteoblasts • Receptor activator of nuclear factor kB ligand • 1,25(OH)2D3 -mediated signaling in regulating the activity of chondrocytes & osteoblasts • During endochondral bone formation & bone homeostasis

  25. Aberrant growth plate development in VDR-deficient mice appears before the onset of hypocalcemia • High Ca diet corrected all aspects of the phenotype of CYP27B1-deficient mice, except long bone growth - Endocr Rev 2008;29: 726–776

  26. Mice lacking VDR expression in chondrocytes • Normal growth plate • But develop a transient phenotype of increased bone volume postnatally • Due to decreased expression of the angiogenic factor VEGF & the osteoclastogenic factor receptor activator of nuclear factor kB ligand in chondrocytes - J Clin Invest 2006; 116: 3150–3159

  27. 1,25(OH)2D3 -mediated signaling in chondrocytes • Necessary for timely vascular invasion & osteoclastogenesis during bone growth

  28. VITAMIN D & CANCER

  29. Several large-scale epidemiological studies have shown an inverse correlation between exposure to sunlight (the major source of vitamin D) or vitamin D intake & risk of colorectal, breast, & prostate cancer

  30. Colorectal cancer risk • Am J Prev Med 2007; 32: 210–216 • Meta-analysis • 51% lower incidence of colorectal ca • Highest serum 25(OH)D3 quintile (82 nmol/l) compared to the lowest quintile (<=30 nmol/l) • Aliment Pharmacol Ther 2009; 30:113–125 • Meta-analysis • Lower serum 25(OH)D3 inversely associated with colorectal cancer

  31. Am J Prev Med 2007; 32: 210–216

  32. Am J Prev Med 2007; 32: 210–216

  33. Aliment Pharmacol Ther 2009; 30:113–125

  34. NEJM 2006; 354: 684–696 • Randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women from 40 Women’s Health Initiative centers, combined treatment of vitamin D3 (400 IU per day) & Ca • Not decrease colon cancer risk • Am J Clin Nutr 2007; 85: 1586–1591 • Much smaller RCT • 1100 IU per day of vitamin D3 + Ca • Decreased the overall cancer risk

  35. Am J Clin Nutr 2007; 85: 1586–1591 RR=0.232, P<0.005 RR=0.587, P=0.147

  36. Breast cancer risk • Positive study in the US & Europe • Best Pract Res Clin Endocrinol Metab 2008; 22: 587–599 • UK • Women with 25(OH)D3 levels < 50nmol/l OR=3.54 for breast cancer risk compared with women with levels >50 nmol/l • Negative in other epidemiological studies

  37. Cancer Epidemiol Biomarkers Prev 2005; 14: 1991–1997

  38. Prostate cancer • Association with 25(OH)D3 status less clear than for colorectal cancer • Overall cancer outcome • Association remains ambiguous

  39. Am J Epidemiol 2009; 169:1223–1232

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