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

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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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.

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

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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

Keywords

  • SAR1B
  • Chylomicrons
  • Lipid absorption
  • COPII
  • Anderson disease
  • Chylomicron retention disease