title: 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.
authors.affiliation: Department of Medicine, Division of Genetic Medicine, Vanderbilt University, Light Hall 1165B, Nashville, TN, 37232, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Levic
authors.forename: J R
authors.initials: JR
authors.lastname: Minkel
authors.forename: Wen-Der
authors.initials: WD
authors.lastname: Wang
authors.forename: Witold M
authors.initials: WM
authors.lastname: Rybski
authors.forename: David B
authors.initials: DB
authors.lastname: Melville
authors.forename: Ela W
authors.initials: EW
authors.lastname: Knapik
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning / Q000235:genetics; D001842:Bone and Bones / Q000196:embryology / Q000378:metabolism; D001921:Brain / Q000196:embryology / Q000378:metabolism; D004195:Disease Models, Animal; D041981:Gastrointestinal Tract / Q000196:embryology / Q000378:metabolism; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000235:genetics* / Q000378:metabolism*; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000235:genetics*; D008286:Malabsorption Syndromes / Q000235:genetics* / Q000378:metabolism*; D020559:Monomeric GTP-Binding Proteins / Q000172:deficiency*; D038081:Organogenesis / Q000235:genetics; D010641:Phenotype; D015027:Zebrafish
chemical_list: D020559:Monomeric GTP-Binding Proteins