| Lipids in Health and Disease | |
| Vitamin D receptor regulates intestinal proteins involved in cell proliferation, migration and stress response | |
| Gabriele I Stangl4  Bettina König4  Kristin Schulz1  Angelika Schierhorn3  Christina Cordes2  Susann Weinholz2  Alexandra Schutkowski4  Hagen Kühne4  | |
| [1] Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, D-06112 Halle (Saale), Germany;Department of Applied Biosciences and Process Engineering, Anhalt University of Applied Sciences, D-06366 Köthen, Germany;Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, D-06120 Halle (Saale), Germany;Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Von-Danckelmann-Platz 2, D-06120 Halle (Saale), Germany | |
| 关键词: Stress response; Mice; Cell adhesion; Laminin receptor; Proteomics; Small intestine; VDR-deficiency; | |
| Others : 805420 DOI : 10.1186/1476-511X-13-51 |
|
| received in 2014-01-10, accepted in 2014-03-11, 发布年份 2014 | |
PDF
|
|
【 摘 要 】
Background
Genome-wide association studies found low plasma levels of 25-hydroxyvitamin D and vitamin D receptor (VDR) polymorphisms associated with a higher prevalence of pathological changes in the intestine such as chronic inflammatory bowel diseases.
Methods
In this study, a proteomic approach was applied to understand the overall physiological importance of vitamin D in the small intestine, beyond its function in calcium and phosphate absorption.
Results
In total, 569 protein spots could be detected by two-dimensional-difference in-gel electrophoresis (2D-DIGE), and 82 proteins were considered as differentially regulated in the intestinal mucosa of VDR-deficient mice compared to that of wildtype (WT) mice. Fourteen clearly detectable proteins were identified by MS/MS and further analyzed by western blot and/or real-time RT-PCR. The differentially expressed proteins are functionally involved in cell proliferation, cell adhesion and cell migration, stress response and lipid transport. Mice lacking VDR revealed higher levels of intestinal proteins associated with proliferation and migration such as the 37/67 kDa laminin receptor, collagen type VI (alpha 1 chain), keratin-19, tropomyosin-3, adseverin and higher levels of proteins involved in protein trafficking and stress response than WT mice. In contrast, proteins that are involved in transport of bile and fatty acids were down-regulated in small intestine of mice lacking VDR compared to WT mice. However, plasma and liver concentrations of cholesterol and triglycerides were not different between the two groups of mice.
Conclusion
Collectively, these data imply VDR as an important factor for controlling cell proliferation, migration and stress response in the small intestine.
【 授权许可】
2014 Kühne et al.; licensee BioMed Central Ltd.
【 预 览 】
| Files | Size | Format | View |
|---|---|---|---|
| 20140708075733435.pdf | 848KB | ||
| Figure 4. | 43KB | Image | |
| Figure 3. | 34KB | Image | |
| Figure 2. | 75KB | Image | |
| Figure 1. | 62KB | Image |
【 图 表 】
Figure 1.
Figure 2.
Figure 3.
Figure 4.
【 参考文献 】
- [1]Wacker M, Holick MF: Vitamin D - effects on skeletal and extraskeletal health and the need for supplementation. Nutrients 2013, 5:111-148.
- [2]Holick MF: The vitamin D deficiency pandemic and consequences for nonskeletal health: mechanisms of action. Mol Aspects Med 2008, 29:361-368.
- [3]Hossein-nezhad A, Spira A, Holick MF: Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: a randomized double-blind clinical trial. PLoS One 2013, 8:e58725.
- [4]Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C, Demay M: Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev 2008, 29:726-776.
- [5]Sun J: Vitamin D and mucosal immune function. Curr Opin Gastroenterol 2010, 26:591-595.
- [6]Christakos S: Mechanism of action of 1,25-dihydroxyvitamin D3 on intestinal calcium absorption. Rev Endocr Metab Disord 2012, 13:39-44.
- [7]Kong J, Zhang Z, Musch MW, Ning G, Sun J, Hart J, Bissonnette M, Li YC: Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol 2008, 294:G208-G216.
- [8]Froicu M, Cantorna MT: Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol 2007, 8:5. BioMed Central Full Text
- [9]Froicu M, Zhu Y, Cantorna MT: Vitamin D receptor is required to control gastrointestinal immunity in IL-10 knockout mice. Immunology 2006, 117:310-318.
- [10]Ooi JH, Chen J, Cantorna MT: Vitamin D regulation of immune function in the gut: why do T cells have vitamin D receptors? Mol Aspects Med 2012, 33:77-82.
- [11]Sadava D, Remer T, Petersen K: Hyperplasia, hyperproliferation and decreased migration rate of colonic epithelial cells in mice fed a diet deficient in vitamin D. Biol Cell 1996, 87:113-115.
- [12]Kállay E, Bareis P, Bajna E, Kriwanek S, Bonner E, Toyokuni S, Cross HS: Vitamin D receptor activity and prevention of colonic hyperproliferation and oxidative stress. Food Chem Toxicol 2002, 40:1191-1196.
- [13]Holt PR, Arber N, Halmos B, Forde K, Kissileff H, Mcglynn KA, Moss SF, Fan K, Yang K: Colonic epithelial cell proliferation decreases with increasing levels of serum 25-hydroxy vitamin D. Cancer Epidemiol Biomarkers Prev 2002, 11:113-119.
- [14]Jørgensen SP, Hvas CL, Agnholt J, Christensen LA, Heickendorff L, Dahlerup JF: Active Crohn’s disease is associated with low vitamin D levels. J Crohns Colitis 2013, 7:e407-e413.
- [15]Gilman J, Shanahan F, Cashman KD: Determinants of vitamin D status in adult Crohn’s disease patients, with particular emphasis on supplemental vitamin D use. Eur J Clin Nutr 2006, 60:889-896.
- [16]McCarthy D, Duggan P, O’Brien M, Kiely M, McCarthy J, Shanahan F, Cashman KD: Seasonality of vitamin D status and bone turnover in patients with Crohn’s disease. Aliment Pharmacol Ther 2005, 21:1073-1083.
- [17]Garg M, Lubel JS, Sparrow MP, Holt SG, Gibson PR: Review article: vitamin D and inflammatory bowel disease–established concepts and future directions. Aliment Pharmacol Ther 2012, 36:324-344.
- [18]Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Burrell A, Handunnetthi L, Handel AE, Disanto G, Orton S-M, Watson CT, Morahan JM, Giovannoni G, Ponting CP, Ebers GC, Knight JC: A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res 2010, 20:1352-1360.
- [19]Liu W, Chen Y, Golan MA, Annunziata ML, Du J, Dougherty U, Kong J, Musch M, Huang Y, Pekow J, Zheng C, Bissonnette M, Hanauer SB, Li YC: Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis. J Clin Invest 2013, 123:3983-3996.
- [20]Zhao H, Zhang H, Wu H, Li H, Liu L, Guo J, Li C, Shih DQ, Zhang X: Protective role of 1,25(OH)2 vitamin D3 in the mucosal injury and epithelial barrier disruption in DSS-induced acute colitis in mice. BMC Gastroenterol 2012, 12:57. BioMed Central Full Text
- [21]Kim J-H, Yamaori S, Tanabe T, Johnson CH, Krausz KW, Kato S, Gonzalez FJ: Implication of intestinal VDR deficiency in inflammatory bowel disease. Biochim Biophys Acta 1830, 2013:2118-2128.
- [22]D’Errico I, Moschetta A: Nuclear receptors, intestinal architecture and colon cancer: an intriguing link. Cell Mol Life Sci 2008, 65:1523-1543.
- [23]Pereira F, Larriba MJ, Muñoz A: Vitamin D and colon cancer. Endocr Relat Cancer 2012, 19:R51-R71.
- [24]Wang Y, Zhu J, DeLuca HF: Where is the vitamin D receptor? Arch Biochem Biophys 2012, 523:123-133.
- [25]Haussler MR, Whitfield GK, Kaneko I, Haussler CA, Hsieh D, Hsieh J-C, Jurutka PW: Molecular mechanisms of vitamin D action. Calcif Tissue Int 2013, 92:77-98.
- [26]Nagpal S, Na S, Rathnachalam R: Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 2005, 26:662-687.
- [27]Givant-Horwitz V, Davidson B, Reich R: Laminin-induced signaling in tumor cells: the role of the Mr 67,000 laminin receptor. CANCER Res 2004, 64:3572-3579.
- [28]Vana K, Zuber C, Pflanz H, Kolodziejczak D, Zemora G, Weiss S: LRP/LR as an alternative promising target in therapy of prion diseases, alzheimer’s disease and cancer. Infect Disord Drug Targets 2009, 9:69-80.
- [29]Omar A, Reusch U, Knackmuss S, Little M, Weiss SFT: Anti-LRP/LR-specific antibody IgG1-iS18 significantly reduces adhesion and invasion of metastatic lung, cervix, colon and prostate cancer cells. J Mol Biol 2012, 419:102-109.
- [30]Khalfaoui T, Groulx J-F, Sabra G, Guezguez A, Basora N, Vermette P, Beaulieu J-F: Laminin receptor 37/67LR regulates adhesion and proliferation of normal human intestinal epithelial cells. PLoS One 2013, 8:e74337.
- [31]Krishnan AV, Feldman D: Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol 2011, 51:311-336.
- [32]Kallay E, Pietschmann P, Toyokuni S, Bajna E, Hahn P, Mazzucco K, Bieglmayer C, Kato S, Cross HS: Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage. Carcinogenesis 2001, 22:1429-1435.
- [33]Groulx J-F, Gagné D, Benoit YD, Martel D, Basora N, Beaulieu J-F: Collagen VI is a basement membrane component that regulates epithelial cell-fibronectin interactions. Matrix Biol 2011, 30:195-206.
- [34]Quaronis A, Calnek D, Quaroni E, Chandler JS: Keratin expression in rat intestinal crypt and villus cells. J Biol Chem 1991, 266:11923-11931.
- [35]Hein Z, Schmidt S, Zimmer K-P, Naim HY: The dual role of annexin II in targeting of brush border proteins and in intestinal cell polarity. Differentiation 2011, 81:243-252.
- [36]Ishikawa R, Yamashiro S, Matsumura M: Differential modulation of actin-severing activity of gelsolin by multiple isoforms of cultured rat cell tropomyosin. J Biol Chem 1989, 264:7490-7497.
- [37]Lees JG, Bach CTT, Neill GMO: Interior decoration tropomyosin in actin dynamics and cell migration. Cell Adh Migr 2011, 5:181-186.
- [38]Max D, Brandsch C, Schumann S, Kühne H, Frommhagen M, Schutkowski A, Hirche F, Staege MS, Stangl GI: Maternal vitamin D deficiency causes smaller muscle fibers and altered transcript levels of genes involved in protein degradation, myogenesis, and cytoskeleton organization in the newborn rat. Mol Nutr Food Res 2013, 25:1-10.
- [39]Pendás-Franco N, González-Sancho JM, Suárez Y, Aguilera O, Steinmeyer A, Gamallo C, Berciano MT, Lafarga M, Muñoz A: Vitamin D regulates the phenotype of human breast cancer cells. Differentiation 2007, 75:193-207.
- [40]Brackman D, Trydal T, Lillehaug AD JR: Reorganization of the cytoskeleton and morphological changes induced by 1,25-dihydroxyvitamin D3 in C3H/10T1/2 mouse embryo fibroblasts: relation to inhibition of proliferation. Exp Cell Res 1992, 201:485-493.
- [41]Riek AE, Oh J, Sprague JE, Timpson A, de las Fuentes L, Bernal-Mizrachi L, Schechtman KB, Bernal-Mizrachi C: Vitamin D suppression of endoplasmic reticulum stress promotes an antiatherogenic monocyte/macrophage phenotype in type 2 diabetic patients. J Biol Chem 2012, 287:38482-38494.
- [42]Noyan T, Balaharoğlu R, Kömüroğlu U: The oxidant and antioxidant effects of 25-hydroxyvitamin D3 in liver, kidney and heart tissues of diabetic rats. Clin Exp Med 2005, 5:31-36.
- [43]Hamden K, Carreau S, Jamoussi K, Miladi S, Lajmi S, Aloulou D, Ayadi F, Elfeki A: 1Alpha,25 dihydroxyvitamin D3: therapeutic and preventive effects against oxidative stress, hepatic, pancreatic and renal injury in alloxan-induced diabetes in rats. J Nutr Sci Vitaminol (Tokyo) 2009, 55:215-222.
- [44]Meyer H, Bug M, Bremer S: Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat Cell Biol 2012, 14:117-123.
- [45]Marzec M, Eletto D, Argon Y: GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum. Biochim Biophys Acta 1823, 2012:774-787.
- [46]Liu T, Daniels CK, Cao S: Comprehensive review on the HSC70 functions, interactions with related molecules and involvement in clinical diseases and therapeutic potential. Pharmacol Ther 2012, 136:354-374.
- [47]Pickering AM, Davies KJA: Differential roles of proteasome and immunoproteasome regulators Pa28αβ, Pa28γ and Pa200 in the degradation of oxidized proteins. Arch Biochem Biophys 2012, 523:181-190.
- [48]Gardino AK, Yaffe MB: 14-3-3 proteins as signaling integration points for cell cycle control and apoptosis. Semin Cell Dev Biol 2011, 22:688-695.
- [49]Kleppe R, Martinez A, Døskeland SO, Haavik J: The 14-3-3 proteins in regulation of cellular metabolism. Semin Cell Dev Biol 2011, 22:713-719.
- [50]Angrand P-O, Segura I, Völkel P, Ghidelli S, Terry R, Brajenovic M, Vintersten K, Klein R, Superti-Furga G, Drewes G, Kuster B, Bouwmeester T, Acker-Palmer A: Transgenic mouse proteomics identifies new 14-3-3-associated proteins involved in cytoskeletal rearrangements and cell signaling. Mol Cell Proteomics 2006, 5:2211-2227.
- [51]Tian Q, Feetham MC, Tao WA, He XC, Li L, Aebersold R, Hood L: Proteomic analysis identifies that 14-3-3 interacts with b-catenin and facilitates its activation by Akt. Proc Natl Acad Sci U S A 2004, 101:15370-15375.
- [52]Palmer HG: Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol 2001, 154:369-388.
- [53]Schmidt DR, Holmstrom SR, Fon Tacer K, Bookout AL, Kliewer SA, Mangelsdorf DJ: Regulation of bile acid synthesis by fat-soluble vitamins A and D. J Biol Chem 2010, 285:14486-14494.
- [54]Kramer W, Corsiero D, Friedrich M, Girbig F, Stengelin S, Weyland C: Intestinal absorption of bile acids: paradoxical behaviour of the 14 kDa ileal lipid-binding protein in differential photoaffinity labelling. Biochem J 1998, 333:335-341.
- [55]Agellon L, Toth M, Thomson A: Intracellular lipid binding proteins of the small intestine. Mol Cell Biochem 2002, 239:79-82.
- [56]Wong KE, Szeto FL, Zhang W, Ye H, Kong J, Zhang Z, Sun XJ, Li YC: Involvement of the vitamin D receptor in energy metabolism: regulation of uncoupling proteins. Am J Physiol Endocrinol Metab 2009, 296:E820-828.
- [57]Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976, 72:248-254.
- [58]Neuhoff V, Arold N, Taube D, Ehrhardt W: Improved staining of proteins in polyacrylamide gels including isoelectric focusing gels with clear background at nanogram sensitivity using Coomassie Brilliant Blue G-250 and R-250. Electrophoresis 1988, 6:255-262.
- [59]Mascot search engine [http://www.matrixscience.com webcite]
- [60]Bettzieche A, Brandsch C, Eder K, Stangl GI: Lupin protein acts hypocholesterolemic and increases milk fat content in lactating rats by influencing the expression of genes involved in cholesterol homeostasis and triglyceride synthesis. Mol Nutr Food Res 2009, 53:1134-1142.
- [61]Bettzieche A, Brandsch C, Schmidt M, Weisse K, Eder K, Stangl GI: Differing effect of protein isolates from different cultivars of blue lupin on plasma lipoproteins of hypercholesterolemic rats. Biosci Biotechnol Biochem 2008, 72:3114-3121.
- [62]Pfaffl MW: A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001, 29:e45.
- [63]Hara A, Radin N: Lipid extraction of tissues with a low-toxicity solvent. Anal Biochem 1978, 90:420-426.
- [64]De Hoff JL, Davidson LM, Kritchevsky D: An exzymatic assay for determining free and total cholesterol in tissue. Clin Chem 1978, 435:433-435.
- [65]König B, Koch A, Spielmann J, Hilgenfeld C, Stangl GI, Eder K: Activation of PPARalpha lowers synthesis and concentration of cholesterol by reduction of nuclear SREBP-2. Biochem Pharmacol 2007, 73:574-585.
PDF