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 OJEMD  Vol.2 No.4 , November 2012
The Liver X-Receptor (Lxr) Governs Lipid Homeostasis in Zebrafish during Development
Abstract: The liver X-receptors (LXRs) act as cholesterol sensors and participate in the regulation of lipid and cholesterol metabolism. The objective of this study was to determine the role of LXR during development using the zebrafish model. By in situ hybridization we showed distinct expression of lxr in the brain and the retina in the developing and adult zebrafish. Lxr ligand activation affected the expression of genes involved in lipid metabolism in zebrafish adult brain and eye as well as in zebrafish embryos. Morpholino knock down of lxr resulted in an overall impaired lipid deposition as determined by oil red O staining particularly in the head and around the eyes, and to significantly elevated levels of both total and free cholesterol in the yolk of lxr morphant embryos. The expression of genes involved in lipid and cholesterol metabolism was also changed in the lxr morphants. Furthermore, alcian blue staining revealed malformation of the pharyngeal skeleton in the lxr morphant. Our data show that lxr is an important component of the regulatory network governing the lipid homeostasis during zebrafish development, which in turn may support a role of lxr for normal development of the central nervous sytem, including the retina.
Cite this paper: A. Archer, S. Srinivas Kitambi, S. L. Hallgren, M. Pedrelli, K. Håkan Olsén, A. Mode and J. Gustafsson, "The Liver X-Receptor (Lxr) Governs Lipid Homeostasis in Zebrafish during Development," Open Journal of Endocrine and Metabolic Diseases, Vol. 2 No. 4, 2012, pp. 74-81. doi: 10.4236/ojemd.2012.24012.
References

[1]   S. Bertrand, B. Thisse, R. Tavares, et al., “Unexpected Novel Relational Links Uncovered by Extensive Developmental Profiling of Nuclear Receptor Expression,” PLoS Genetics, Vol. 3, No. 11, 2007, p. e188. doi:10.1371/journal.pgen.0030188

[2]   B. A. Janowski, M. J. Grogan, S. A. Jones, et al., “Structural Requirements of Ligands for the Oxysterol Liver X Receptors LXRalpha and LXRbeta,” Proceedings of the National Acadamy of Sciences of the USA, 5 January 1999, pp. 266-271. doi:10.1073/pnas.96.1.266

[3]   G. Hoffmann, K. M. Gibson, I. K. Brandt, P. I. Bader, R. S. Wappner and L. Sweetman, “Mevalonic Aciduria—An Inborn Error of Cholesterol and Nonsterol Isoprene Biosynthesis,” New England Journal of Medicine, Vol. 314, No. 25. 1986, pp. 1610-1614. doi:10.1056/NEJM198606193142504

[4]   D. W. Smith, L. Lemli and J. M. Opitz, “A Newly Recognized Syndrome of Multiple Congenital Anomalies,” The Journal of Pediatrics, Vol. 64, 1964, pp. 210-217. doi:10.1016/S0022-3476(64)80264-X

[5]   N. Y. Kalaany, K. C. Gauthier, A. M. Zavacki, et al., “LXRs Regulate the Balance between Fat Storage and Oxidation,” Cell Metabolism, Vol. 1, No. 4, 2005, pp. 231-244. doi:10.1016/j.cmet.2005.03.001

[6]   L. Wang, G. U. Schuster, K. Hultenby, Q. Zhang, S. Andersson and J. A. Gustafsson, “Liver X Receptors in the Central Nervous System: From Lipid Homeostasis to Neuronal Degeneration,” Proceedings of the National Acadamy of Sciences of the USA, 15 October 2002, pp. 13878-13883. doi:10.1073/pnas.172510899

[7]   X. Fan, H. J. Kim, D. Bouton, M. Warner and J. A. Gustafsson, “Expression of Liver X Receptor Beta Is Essential for Formation of Superficial Cortical Layers and Migration of Later-Born Neurons,” Proceedings of the National Acadamy of Sciences of the USA, 9 September 2008, pp. 13445-13450. doi:10.1073/pnas.0806974105

[8]   B. A. Laffitte, L. C. Chao, J. Li, et al., “Activation of Liver X Receptor Improves Glucose Tolerance through Coordinate Regulation of Glucose Metabolism in Liver and Adipose Tissue,” Proceedings of the National Acadamy of Sciences of the USA, 29 April 2003, pp. 5419-5424. doi:10.1073/pnas.0830671100

[9]   E. J. Flynn, C. M. Trent and J. F. Rawls, “Ontogeny and Nutritional Control of Adipogenesis in Zebrafish (Danio rerio),” Journal of LIPID Research, Vol. 50, No. 8, 2009, pp. 1641-1652. doi:10.1194/jlr.M800590-JLR200

[10]   A. Archer, G. Lauter, G. Hauptmann, A. Mode and J. A. Gustafsson, “Transcriptional Activity and Developmental Expression of Liver X Receptor (lxr) in Zebrafish,” Developmental Dynamics, Vol. 237, No. 4, 2008, pp. 1090-1098. doi:10.1002/dvdy.21476

[11]   S. Bertrand, F. G. Brunet, H. Escriva, G. Parmentier, V. Laudet and M. Robinson-Rechavi, “Evolutionary Genomics of Nuclear Receptors: From Twenty-Five Ancestral Genes to Derived Endocrine Systems,” Molecular Biology and Evolution, Vol. 21, No. 10, 2004, pp. 1923-1937. doi:10.1093/molbev/msh200

[12]   E. J. Reschly, N. Ai, W. J. Welsh, S. Ekins, L. R. Hagey and M. D. Krasowski, “Ligand Specificity and Evolution of Liver X Receptors,” The Journal of Steroid Biochemistry and Molecular Biology, Vol. 110, No. 1-2, 2008, pp. 83-94. doi:10.1016/j.jsbmb.2008.02.007

[13]   C. B. Kimmel, W. W. Ballard, S. R. Kimmel, B. Ullmann and T. F. Schilling, “Stages of Embryonic Development of the Zebrafish,” Developmental Dynamics, Vol. 203, No. 3, 1995, pp. 253-310. doi:10.1002/aja.1002030302

[14]   U. Langheinrich, E. Hennen, G. Stott and G. Vacun, “Zebrafish as a Model Organism for the Identification and Characterization of Drugs and Genes Affecting p53 Signaling,” Current Biology, Vol. 12, No. 23, 2002, pp. 2023-2028. doi:10.1016/S0960-9822(02)01319-2

[15]   B. Tucker and M. Lardelli, “A Rapid Apoptosis Assay Measuring Relative Acridine Orange Fluorescence in Zebrafish Embryos,” Zebrafish, Vol. 4, No. 2, 2007, pp. 113-116. doi:10.1089/zeb.2007.0508

[16]   M. B. Walker and C. B. Kimmel, “A Two-Color Acid-Free Cartilage and Bone Stain for Zebrafish Larvae,” Biotechnic and Histochemistry, Vol. 82, No. 1, 2007, pp. 23-28. doi:10.1080/10520290701333558

[17]   K. Schlombs, T. Wagner and J. Scheel, “Site-1 Protease Is Required for Cartilage Development in Zebrafish,” Proceedings of the National Acadamy of Sciences of the USA, 2003, pp. 14024-14029. doi:10.1073/pnas.2331794100

[18]   M. Korach-Andre, A. Archer, C. Gabbi, et al., “Liver X Receptors Regulate de Novo Lipogenesis in a Tissue-Specific Manner in C57BL/6 Female Mice,” American Journal of Physiology Endocrinology and Metabolism, Vol. 301, No. 1, 2011, pp. E210-E222. doi:10.1152/ajpendo.00541.2010

[19]   H. J. Hsu, N. C. Hsu, M. C. Hu and B. C. Chung, “Steroidogenesis in Zebrafish and Mouse Models,” Molecular and Cellular Endocrinology, Vol. 248, No. 1-2, 2006, pp. 160-163. doi:10.1016/j.mce.2005.10.011

[20]   D. Lutjohann, O. Breuer, G. Ahlborg, et al., “Cholesterol Homeostasis in Human Brain: Evidence for an Age-Dependent Flux of 24S-Hydroxycholesterol from the Brain into the Circulation,” Proceedings of the National Acadamy of Sciences of the USA, 1996, pp. 9799-9804. doi:10.1073/pnas.93.18.9799

[21]   D. J. Peet, B. A. Janowski and D. J. Mangelsdorf, “The LXRs: A New Class of Oxysterol Receptors,” Current Opinion in Genetics & Development, Vol. 8, No. 5, 1998, pp. 571-575. doi:10.1016/S0959-437X(98)80013-0

[22]   J. R. Schultz, H. Tu, A. Luk, et al., “Role of LXRs in Control of Lipogenesis,” Genes and Development, Vol. 14, No. 22, 2000, pp. 2831-2838. doi:10.1101/gad.850400

[23]   H. Sukardi, X. Zhang, E. Y. Lui, et al., “Liver X Receptor Agonist T0901317 Induced Liver Perturbation in Zebrafish: Histological, Gene Set Enrichment and Expression Analyses,” Biochimica et Biophysica Acta (BBA)—General Subjects, Vol. 1820, No. 1, 2011, pp. 33-43. doi:10.1016/j.bbagen.2011.10.009

[24]   D. R. Tocher, A. J. Fraser, J. R. Sargent and J. C. Gamble, “Lipid Class Composition during Embryonic and Early Larval Development in Atlantic Herring,” Lipids, Vol. 20, No. 2, 1985, pp. 84-89. doi:10.1007/BF02534210

[25]   D. R. Tocher, A. J. Fraser, J. R. Sargent and J. C. Gamble, “Fatty Acid Composition of Phospholipids and Neutral Lipids during Embryonic and Early Larval Development in Atlantic Herring,” Lipids, Vol. 20, No. 2, 1985, pp. 69-74. doi:10.1007/BF02534210

[26]   J. M. Vernier and M. F. Sire, “Lipoprotéines de très Basse Densité et Glycogène Dans le Syncytium Vitellin, L’épithélium Intestinal et le Foie, Aux Stades Précoces du Developement Embryonnaire Chez la Truite Arc-en-Ciel,” Biologie cellulaire, Vol. 29, 1977, pp. 45-54.

[27]   E. M. Madsen, M. L. Lindegaard, C. B. Andersen, P. Damm and L. B. Nielsen, “Human Placenta Secretes Apolipoprotein B-100-Containing Lipoproteins,” The Journal of Biological Chemistry, Vol. 279, No. 53, 2004, pp. 55271-55276. doi:10.1074/jbc.M411404200

[28]   Y. Terasawa, S. J. Cases, J. S. Wong, et al., “Apolipoprotein B-Related Gene Expression and Ultrastructural Characteristics of Lipoprotein Secretion in Mouse Yolk Sac during Embryonic Development,” Journal of Lipid Research, Vol. 40, No. 11, 1999, pp. 1967-1977.

[29]   A. Grefhorst, B. M. Elzinga, P. J. Voshol, et al., “Stimulation of Lipogenesis by Pharmacological Activation of the Liver X Receptor Leads to Production of Large, Triglyceride-Rich Very Low Density Lipoprotein Particles,” Journal of Biological Chemistry, Vol. 277, No. 37, 2002, pp. 34182-34190. doi:10.1074/jbc.M204887200

[30]   J. Stefulj, U. Panzenboeck, T. Becker, et al., “Human Endothelial Cells of the Placental Barrier Efficiently Deliver Cholesterol to the Fetal Circulation via ABCA1 and ABCG1,” Circulation Research, Vol. 104, No. 5, 2009, pp. 600-608. doi:10.1161/CIRCRESAHA.108.185066

[31]   J. J. Repa, H. Li, T. C. Frank-Cannon, et al., “Liver X Receptor Activation Enhances Cholesterol Loss from the Brain, Decreases Neuroinflammation, and Increases Survival of the NPC1 Mouse,” The Journal of Neuroscience, Vol. 27, No. 52, 2007, pp. 14470-14480. doi:10.1523/JNEUROSCI.4823-07.2007

[32]   P. Sacchetti, K. M. Sousa, A. C. Hall, et al., “Liver X Receptors and Oxysterols Promote Ventral Midbrain Neurogenesis in Vivo and in Human Embryonic Stem Cells,” Cell Stem Cell, Vol. 5, No. 4, pp. 409-419. doi:10.1016/j.stem.2009.08.019

[33]   M. Futter, H. Diekmann, E. Schoenmakers, O. Sadiq, K. Chatterjee and D. C. Rubinsztein, “Wild-Type but Not Mutant Huntingtin Modulates the Transcriptional Activity of Liver X Receptors,” Journal of Medical Genetics, Vol. 46, No. 7, 2009, pp. 438-446. doi:10.1136/jmg.2009.066399

[34]   S. Wu and F. De Luca, “Role of Cholesterol in the Regulation of Growth Plate Chondrogenesis and Longitudinal Bone Growth,” Journal of Biological Chemistry, Vol. 279, No. 6, 2004, pp. 4642-4647. doi:10.1136/jmg.2009.066399

[35]   P. Haffter, M. Granato, M. Brand, et al., “The Identification of Genes with Unique and Essential Functions in the Development of the Zebrafish, Danio Rerio,” Development, Vol. 123, 1996, pp. 1-36. doi:10.1074/jbc.M305518200

[36]   X. Meng, M. B. Noyes, L. J. Zhu, N. D. Lawson and S. A. Wolfe, “Targeted Gene Inactivation in Zebrafish Using Engineered Zinc-Finger Nucleases,” Nature Biotechnology, Vol. 26, No. 6, 2008, pp. 695-701. doi:10.1038/nbt1398

 
 
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