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Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease

Journal of Molecular Medicine volume 93, pages 165–176 (2015)Cite this article

Abstract

Anderson disease (ANDD) or chylomicron retention disease (CMRD) is a rare, hereditary lipid malabsorption syndrome associated with mutations in the SAR1B gene that is characterized by failure to thrive and hypocholesterolemia. Although the SAR1B structure has been resolved and its role in formation of coat protein II (COPII)-coated carriers is well established, little is known about the requirement for SAR1B during embryogenesis. To address this question, we have developed a zebrafish model of Sar1b deficiency based on antisense oligonucleotide knockdown. We show that zebrafish sar1b is highly conserved among vertebrates; broadly expressed during development; and enriched in the digestive tract organs, brain, and craniofacial skeleton. Consistent with ANDD symptoms of chylomicron retention, we found that dietary lipids in Sar1b-deficient embryos accumulate in enterocytes. Transgenic expression analysis revealed that Sar1b is required for growth of exocrine pancreas and liver. Furthermore, we found abnormal differentiation and maturation of craniofacial cartilage associated with defects in procollagen II secretion and absence of select, neuroD-positive neurons of the midbrain and hindbrain. The model presented here will help to systematically dissect developmental roles of Sar1b and to discover molecular and cellular mechanisms leading to organ-specific ANDD pathology.

Key messages

  • Sar1b depletion phenotype in zebrafish resembles Anderson disease deficits.

  • Sar1b deficiency results in multi-organ developmental deficits.

  • Sar1b is required for dietary cholesterol uptake into enterocytes.

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References

  1. Abumrad NA, Davidson NO (2012) Role of the gut in lipid homeostasis. Physiol Rev 92:1061–1085

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Iqbal J, Hussain MM (2009) Intestinal lipid absorption. Am J Physiol Endocrinol Metab 296:E1183–E1194

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Miller EA, Barlowe C (2010) Regulation of coat assembly—sorting things out at the ER. Curr Opin Cell Biol 22:447–453

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Siddiqi SA, Gorelick FS, Mahan JT, Mansbach CM (2003) COPII proteins are required for Golgi fusion but not for endoplasmic reticulum budding of the pre-chylomicron transport vesicle. J Cell Sci 116:415–427

    Article  CAS  PubMed  Google Scholar 

  5. Walther TC, Farese RV (2012) Lipid droplets and cellular lipid metabolism. Annu Rev Biochem 81:687–714

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Mansbach CM, Siddiqi SA (2010) The biogenesis of chylomicrons. Annu Rev Physiol 72:315–333

    Article  CAS  PubMed  Google Scholar 

  7. Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, Eichenbaum-Voline S, Rudling M, Myrdal U, Annesi G, Naik S et al (2003) Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat Genet 34:29–31

    Article  CAS  PubMed  Google Scholar 

  8. Georges A, Bonneau J, Bonnefont-Rousselot D, Champigneulle J, Rabès JP, Abifadel M, Aparicio T, Guenedet JC, Bruckert E, Boileau C et al (2011) Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson’s disease (chylomicron retention disease). Orphanet J Rare Dis 6:1

    Article  PubMed Central  PubMed  Google Scholar 

  9. Peretti N, Roy CC, Sassolas A, Deslandres C, Drouin E, Rasquin A, Seidman E, Brochu P, Vohl M-C, Labarge S et al (2009) Chylomicron retention disease: a long term study of two cohorts. Mol Genet Metab 97:136–142

    Article  CAS  PubMed  Google Scholar 

  10. Silvain M, Bligny D, Aparicio T, Laforêt P, Grodet A, Peretti N, Ménard D, Djouadi F, Jardel C, Bégué J et al (2008) Anderson’s disease (chylomicron retention disease): a new mutation in the SARA2 gene associated with muscular and cardiac abnormalities. Clin Genet 74:546–552

    Article  CAS  PubMed  Google Scholar 

  11. Bernard G, Panisset M, Sadikot AF, Chouinard S (2010) Chylomicron retention disease: dystonia as a new clinical feature. Mov Disord 25:1755–1756

    Article  PubMed  Google Scholar 

  12. Schlegel A, Stainier DYR (2006) Microsomal triglyceride transfer protein is required for yolk lipid utilization and absorption of dietary lipids in zebrafish larvae. Biochemistry 45:15179–15187

    Article  CAS  PubMed  Google Scholar 

  13. Anderson JL, Carten JD, Farber SA (2011) Chapter 5—zebrafish lipid metabolism: from mediating early patterning to the metabolism of dietary fat and cholesterol. In: H. William Detrich MW and LIZ (ed) Methods Cell Biol. Academic Press, pp 111–141

  14. Carten JD, Bradford MK, Farber SA (2011) Visualizing digestive organ morphology and function using differential fatty acid metabolism in live zebrafish. Dev Biol 360:276–285

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Maddison LA, Chen W (2012) Nutrient excess stimulates β-cell neogenesis in zebrafish. Diabetes 61:2517–2524

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Walters JW, Anderson JL, Bittman R, Pack M, Farber SA (2012) Visualization of lipid metabolism in the zebrafish intestine reveals a relationship between NPC1L1- mediated cholesterol uptake and dietary fatty acid. Chem Biol 19:913–925

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Kimmel CB, Ballard WW, Kimmel SR, Ullmann B, Schilling TF (1995) Stages of embryonic development of the zebrafish. Dev Dyn 203:253–310

    Article  CAS  PubMed  Google Scholar 

  18. Korzh S, Pan X, Garcia-Lecea M, Winata C, Pan X, Wohland T, Korzh V, Gong Z (2008) Requirement of vasculogenesis and blood circulation in late stages of liver growth in zebrafish. BMC Dev Biol 8:84

    Article  PubMed Central  PubMed  Google Scholar 

  19. Delporte FM, Pasque V, Devos N, Manfroid I, Voz ML, Motte P, Biemar F, Martial JA, Peers B (2008) Expression of zebrafish pax6b in pancreas is regulated by two enhancers containing highly conserved cis-elements bound by PDX1, PBX and PREP factors. BMC Dev Biol 8:53

    Article  PubMed Central  PubMed  Google Scholar 

  20. Sarmah S, Barrallo-Gimeno A, Melville DB, Topczewski J, Solnica-Krezel L, Knapik EW (2010) Sec24D-dependent transport of extracellular matrix proteins is required for zebrafish skeletal morphogenesis. PLoS One 4:e10367. doi: 10.1371/journal.pone.0010367

  21. Sachdev SW, Dietz UH, Oshima Y, Lang MR, Knapik EW, Hiraki Y, Shukunami C (2001) Sequence analysis of zebrafish chondromodulin-1 and expression profile in the notochord and chondrogenic regions during cartilage morphogenesis. Mech Dev 105:157–162

    Article  CAS  PubMed  Google Scholar 

  22. Montero-Balaguer M, Lang MR, Sachdev SW, Knappmeyer C, Stewart RA, De La Guardia A, Hatzopoulos AK, Knapik EW (2006) The mother superior mutation ablates foxd3 activity in neural crest progenitor cells and depletes neural crest derivatives in zebrafish. Dev Dyn 235:3199–3212

    Article  CAS  PubMed  Google Scholar 

  23. Bradford Y, Conlin T, Dunn N, Fashena D, Frazer K, Howe DG, Knight J, Mani P, Martin R, Moxon SAT et al (2011) ZFIN: enhancements and updates to the zebrafish model organism database. Nucleic Acids Res 39:D822–D829

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Müller II, Knapik EW, Hatzopoulos AK (2006) Expression of the protein related to Dan and Cerberus gene—prdc—during eye, pharyngeal arch, somite, and swim bladder development in zebrafish. Dev Dyn 235:2881–2888

    Article  PubMed  Google Scholar 

  25. Müller II, Melville DB, Tanwar V, Rybski WM, Mukherjee A, Shoemaker MB, Wang W-D, Schoenhard JA, Roden DM, Darbar D et al (2013) Functional modeling in zebrafish demonstrates that the atrial-fibrillation-associated gene GREM2 regulates cardiac laterality, cardiomyocyte differentiation and atrial rhythm. Dis Model Mech 6:332–341

    Article  PubMed Central  PubMed  Google Scholar 

  26. Granero-Moltó F, Sarmah S, O’Rear L, Spagnoli A, Abrahamson D, Saus J, Hudson BG, Knapik EW (2008) Goodpasture antigen-binding protein and its spliced variant, ceramide transfer protein, have different functions in the modulation of apoptosis during zebrafish development. J Biol Chem 283:20495–20504

    Article  PubMed Central  PubMed  Google Scholar 

  27. Melville DB, Montero-Balaguer M, Levic DS, Bradley K, Smith JR, Hatzopoulos AK, Knapik EW (2011) The feelgood mutation in zebrafish dysregulates COPII-dependent secretion of select extracellular matrix proteins in skeletal morphogenesis. Dis Model Mech 4:763–776

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Charcosset M, Sassolas A, Peretti N, Roy CC, Deslandres C, Sinnett D, Levy E, Lachaux A (2008) Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein. Mol Genet Metab 93:74–84

    Article  CAS  PubMed  Google Scholar 

  29. Shin D, Shin CH, Tucker J, Ober EA, Rentzsch F, Poss KD, Hammerschmidt M, Mullins MC, Stainier DYR (2007) Bmp and Fgf signaling are essential for liver specification in zebrafish. Development 134:2041–2050

    Article  CAS  PubMed  Google Scholar 

  30. Barrallo-Gimeno A, Holzschuh J, Driever W, Knapik EW (2004) Neural crest survival and differentiation in zebrafish depends on mont blanc/tfap2a gene function. Development 131:1463–1477

    Article  CAS  PubMed  Google Scholar 

  31. Lang MR, Lapierre LA, Frotscher M, Goldenring JR, Knapik EW (2006) Secretory COPII coat component Sec23a is essential for craniofacial chondrocyte maturation. Nat Genet 38:1198–1203

    Article  CAS  PubMed  Google Scholar 

  32. Unlu G, Levic DS, Melville DB, Knapik EW (2014) Trafficking mechanisms of extracellular matrix macromolecules: insights from vertebrate development and human diseases. Int J Biochem Cell Biol 47:57–67

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Siddiqi S, Siddiqi SA, Mansbach CM (2010) Sec24C is required for docking the prechylomicron transport vesicle with the Golgi. J Lipid Res 51:1093–1100

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Melville DB, Knapik EW (2011) Traffic jams in fish bones: ER-to-Golgi protein transport during zebrafish development. Cell Adhes Migr 5:114–118

    Article  Google Scholar 

  35. Vacaru A, Unlu G, Spitzner M, Mione M, Knapik E, Sadler K (2014) In vivo cell biology using zebrafish—providing insights into vertebrate development and disease. J Cell Sci 127:485–495

  36. Schlombs K, Wagner T, Scheel J (2003) Site-1 protease is required for cartilage development in zebrafish. PNAS 100:14024–14029

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Zhu J, Lee B, Buhman KK, Cheng J-X (2009) A dynamic, cytoplasmic triacylglycerol pool in enterocytes revealed by ex vivo and in vivo coherent anti-Stokes Raman scattering imaging. J Lipid Res 50:1080–1089

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Roy CC, Levy E, Green PH, Sniderman A, Letarte J, Buts JP, Orquin J, Brochu P, Weber AM, Morin CL et al (1987) Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B chylomicron retention disease. Gastroenterology 92:390–399

    CAS  PubMed  Google Scholar 

  39. Dannoura AH, Berriot-Varoqueaux N, Amati P, Abadie V, Verthier N, Schmitz J, Wetterau JR, Samson-Bouma M-E, Aggerbeck LP (1999) Anderson’s disease exclusion of apolipoprotein and intracellular lipid transport genes. Arterioscler Thromb Vasc Biol 19:2494–2508

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank C. Guthrie for the excellent animal care, K. Zavalin for expert technical assistance, and Lisette Maddison for sharing plasmids and transgenic fish. We are indebted to Kevin Ess and Antonis Hatzopoulos for critical reading of the manuscript. This manuscript is dedicated in memory of our colleague JR Minkel. This work was supported in part by the Zebrafish Initiative of the Vanderbilt University Academic Venture Capital Fund, the NIH NIDCR grant R01 DE018477 (E.W.K.). D.S.L. was supported by NRSA F31DE022226 and T32HD007502 Training Program in Developmental Biology; D.B.M was supported by T32GM008554, the Cellular, Biochemical and Molecular Sciences Training Program.

Conflict of interest

The authors declare that they do not have any competing or financial interests.

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Authors and Affiliations

  1. Department of Medicine, Division of Genetic Medicine, Vanderbilt University, Light Hall 1165B, Nashville, TN, 37232, USA

    Daniel S. Levic, JR Minkel, Wen-Der Wang, Witold M. Rybski, David B. Melville & Ela W. Knapik

  2. Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA

    Daniel S. Levic, David B. Melville & Ela W. Knapik

  3. Department of Bioagricultural Science, National Chiayi University, Chiayi, 60004, Taiwan

    Wen-Der Wang

  4. Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, 94720-3370, USA

    David B. Melville

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  1. Daniel S. Levic
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Correspondence to Ela W. Knapik.

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Levic, D.S., Minkel, J., Wang, WD. et al. Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease. J Mol Med 93, 165–176 (2015). https://doi.org/10.1007/s00109-014-1247-x

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  • DOI: https://doi.org/10.1007/s00109-014-1247-x

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