ZFIN ID: ZDB-PUB-150107-8
Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease
Levic, D.S., Minkel, J., Wang, W., Rybski, W.M., Melville, D.B., Knapik, E.W.
Date: 2015
Source: Journal of molecular medicine (Berlin, Germany)   93(2): 165-176 (Journal)
Registered Authors: Knapik, Ela W., Melville, David, Wang, Wen-Der
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Body Patterning/genetics
  • Bone and Bones/embryology
  • Bone and Bones/metabolism
  • Brain/embryology
  • Brain/metabolism
  • Disease Models, Animal
  • Gastrointestinal Tract/embryology
  • Gastrointestinal Tract/metabolism
  • Gene Expression
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Humans
  • Hypobetalipoproteinemias/genetics*
  • Hypobetalipoproteinemias/metabolism*
  • Immunohistochemistry
  • Lipid Metabolism/genetics*
  • Malabsorption Syndromes/genetics*
  • Malabsorption Syndromes/metabolism*
  • Monomeric GTP-Binding Proteins/deficiency*
  • Organogenesis/genetics
  • Phenotype
  • Zebrafish
PubMed: 25559265 Full text @ J. Mol. Med.
FIGURES
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 zebra fish 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.
Sar1b depletion phenotype in zebra fish resembles Anderson disease deficits. Sar1b deficiency results in multi-organ developmental deficits. Sar1b is required for dietary cholesterol uptake into enterocytes.