title: LPCAT1 regulates surfactant phospholipid synthesis and is required for transitioning to air breathing in mice.
abstract: Respiratory distress syndrome (RDS), which is the leading cause of death in premature infants, is caused by surfactant deficiency. The most critical and abundant phospholipid in pulmonary surfactant is saturated phosphatidylcholine (SatPC), which is synthesized in alveolar type II cells de novo or by the deacylation-reacylation of existing phosphatidylcholine species. We recently cloned and partially characterized a mouse enzyme with characteristics of a lung lysophosphatidylcholine acyltransferase (LPCAT1) that we predicted would be involved in surfactant synthesis. Here, we describe our studies investigating whether LPCAT1 is required for pulmonary surfactant homeostasis. To address this issue, we generated mice bearing a hypomorphic allele of Lpcat1 (referred to herein as Lpcat1GT/GT mice) using a genetrap strategy. Newborn Lpcat1GT/GT mice showed varying perinatal mortality from respiratory failure, with affected animals demonstrating hallmarks of respiratory distress such as atelectasis and hyaline membranes. Lpcat1 mRNA levels were reduced in newborn Lpcat1GT/GT mice and directly correlated with SatPC content, LPCAT1 activity, and survival. Surfactant isolated from dead Lpcat1GT/GT mice failed to reduce minimum surface tension to wild-type levels. Collectively, these data demonstrate that full LPCAT1 activity is required to achieve the levels of SatPC essential for the transition to air breathing.
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio45229, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Bridges
authors.forename: Machiko
authors.initials: M
authors.lastname: Ikegami
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Brilli
authors.forename: Xueni
authors.initials: X
authors.lastname: Chen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mason
authors.forename: John M
authors.initials: JM
authors.lastname: Shannon
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000378:metabolism*; D000388:Air; D000818:Animals; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000939:Epitopes; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D008954:Models, Biological; D010743:Phospholipids / Q000378:metabolism*; D017433:Protein Structure, Secondary; D011663:Pulmonary Surfactants / Q000378:metabolism; D012119:Respiration; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics
chemical_list: D000939:Epitopes; D010743:Phospholipids; D011663:Pulmonary Surfactants; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C526203:Lpcat1 protein, mouse
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