ABCA3 Is Critical for Lamellar Body Biogenesis in Vivo

Abstract

Mutations in ATP-binding cassette transporter A3 (human ABCA3) protein are associated with fatal respiratory distress syndrome in newborns. We therefore characterized mice with targeted disruption of the ABCA3 gene. Homozygous Abca3 ؊/؊ knock-out mice died soon after birth, whereas most of the wild type, Abca3 ؉/؉ , and heterozygous, Abca3 ؉/؊ , neonates survived. The lungs from E18.5 and E19.5 Abca3 ؊/؊ mice were less mature than wild type. Alveolar type 2 cells from Abca3 ؊/؊ embryos contained no lamellar bodies, and expression of mature SP-B protein was disrupted when compared with the normal lung surfactant system of wild type embryos. Small structural and functional differences in the surfactant system were seen in adult Abca3 ؉/؊ compared with Abca3 ؉/؉ mice. The heterozygotes had fewer lamellar bodies, and the incorporation of radiolabeled substrates into newly synthesized disaturated phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, and phosphatidylserine in both lamellar bodies and surfactant was lower than in Abca3 ؉/؉ mouse lungs. In addition, since the fraction of near term Abca3 ؊/؊ embryos was significantly lower than expected from Mendelian inheritance ABCA3 probably plays roles in development unrelated to surfactant. Collectively, these findings strongly suggest that ABCA3 is necessary for lamellar body biogenesis, surfactant protein-B processing, and lung development late in gestation.Lung surfactant is a complex mixture of 90% lipids, predominantly dipalmitoylphosphatidylcholine, and 10% proteins (SP 2 -A, SP-B, and SP-C) that functions to lower surface tension at the interface between air and the surface lining layer of the alveolar epithelium and prevents lung collapse on end expiration (1-3). The surfactant proteins SP-B and SP-C and lipids are transported to and stored in lamellar bodies, the intracellular secretory organelles of the alveolar epithelial type 2 (AT2) cell through which pulmonary surfactant homeostasis is regulated (4 -6). The final steps in post-translational modification of both SP-B and SP-C occur in lamellar bodies (7-11). One of the striking abnormalities observed in hereditary SP-B deficiency, which is characterized by deficiencies of surfactant quantity and function, is derangement of lamellar body morphology (12), abnormalities that are replicated in the SP-B knock-out mouse (13,14).Fatal deficiencies of lung surfactant in the neonate and interstitial lung disease have recently been associated with mutations in the ATP-binding cassette protein A3 gene (ABCA3) (15,16). ABCA3 is required for normal lamellar body formation in AT2 cells (17). Similarly, the lamellar bodies in electron micrographs from lung tissue of infants with surfactant deficiency and ABCA3 mutations have dense inclusions and are structurally immature (15,18,19). ABCA3 expressed exogenously in cultured cells, in the absence of surfactant proteins, facilitates the transfer of phosphatidylcholine and cholesterol into the lysosomes, the likely progenitor of lamellar bodies, whereas the ...

ABCA12 Maintains the Epidermal Lipid Permeability Barrier by Facilitating Formation of Ceramide Linoleic Esters

“…Previously, we reported the generation of mice lacking ABCA3, and those animals died much more rapidly after birth than did Abca12 Ϫ/Ϫ mice (16). The Abca3 Ϫ/Ϫ mice were never able to inflate their lungs, a finding subsequently confirmed by several other groups, and they failed to form lung lamellar bodies and secrete surfactant into the alveolar space (15,16,35,36). Furthermore, we found ABCA3 to be highly expressed in the lung, whereas ABCA12 is not (Ref.…”

“…ABCA3 mutations cause a form of neonatal respiratory failure that arises from a failure to transport pulmonary phospholipids comprising surfactant from their storage site in the lamellar bodies of alveolar type II cells to the alveolar space (12)(13)(14). This transport process, like the one involving ABCA1, appears to depend on the lipidation of an acceptor amphipathic helical protein, surfactant protein B (15,16). ABCA4 causes Stargadt macular degeneration and visual loss that is associated with a defect in the transport of phosphatidylethanolamine-retinylidene adducts out of retinal pigment epithelial cells (17)(18)(19).…”

Amniotic lamellar body count and congenital diaphragmatic hernia in humans and in a rat model

“…Furthermore, we examined ABCA3 expression by western blotting to assess fetal lung maturation in the rat. ABCA3 protein is expressed predominantly at the limiting membranes of the lamellar bodies in alveolar type II cells (22) and plays an essential role in pulmonary surfactant lipid metabolism, lamellar body biogenesis, surfactant protein-B processing, and lung development late in gestation (23). In the current study, ABAC3 expressions were similar in CDH and non-CDH pups at full term.…”

Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease

“…Exogenous expression of ABCA3 in cultured cells promotes lipid uptake into intracellular vesicles that generate lamellar body-like vesicles (7,18,21). ABCA3 deficiency in human and mice leads to decreased phosphatidylcholine and phosphatidylglycerol in surfactant, dysgenesis of lamellar bodies, and respiratory distress (1,3,8,11,12,27). Considered together, these results indicate that ABCA3 is an essential lipid transporter in surfactant metabolism.…”