LPCAT1 regulates surfactant phospholipid synthesis and is required for transitioning to air breathing in mice.
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.
Bridges
James P
JP
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio45229, USA.
Ikegami
Machiko
M
Brilli
Lauren L
LL
Chen
Xueni
X
Mason
Robert J
RJ
Shannon
John M
JM
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
D000939:Epitopes; D010743:Phospholipids; D011663:Pulmonary Surfactants; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C526203:Lpcat1 protein, mouse
FEBS Lett. 2003 Dec 4;555(2):192-8
14644414
Lung. 1983;161(4):229-34
6310275
Am J Respir Cell Mol Biol. 2007 Oct;37(4):377-8
17872593
Biochim Biophys Acta. 1989 Apr 26;1002(3):277-82
2713380
Biochim Biophys Acta. 1983 Jan 7;750(1):68-77
6297604
Anal Biochem. 1979 Nov 15;100(1):188-97
94515
Monogr Endocrinol. 1986;28:1-354
2869406
Pediatr Res. 1980 Jun;14(6):846-7
7402758
Biochim Biophys Acta. 1998 Nov 19;1408(2-3):79-89
9813251
Am Rev Respir Dis. 1989 Oct;140(4):1033-9
2802366
Chest. 1997 Jun;111(6 Suppl):88S-89S
9184544
Am J Physiol Lung Cell Mol Physiol. 2006 Oct;291(4):L572-9
16632521
Respir Res. 2007 Jul 27;8:55
17662121
Biochim Biophys Acta. 1986 Jun 11;877(1):151-7
3013315
J Clin Invest. 2003 Jul;112(2):244-55
12865412
Can J Biochem Physiol. 1959 Aug;37(8):911-7
13671378
Biochem Biophys Res Commun. 1975 May 5;64(1):128-35
1147917
Nat Cell Biol. 2005 Oct;7(10):999-1006
16179952
J Biol Chem. 2008 Jul 4;283(27):19049-57
18458083
Biochim Biophys Acta. 1972 Jan 27;260(1):70-81
5012455
J Clin Invest. 1995 Jun;95(6):2963-72
7769139
Mol Cell Biol. 2007 Feb;27(3):975-82
17130238
Nat Rev Mol Cell Biol. 2008 Feb;9(2):112-24
18216768
Am J Physiol Lung Cell Mol Physiol. 2000 Sep;279(3):L468-76
10956621
J Biol Chem. 1994 May 6;269(18):13057-60
8175726
Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11724-9
16864775
Mol Cell Biol. 2005 Apr;25(8):3357-63
15798219
J Lipid Res. 2005 Dec;46(12):2624-35
16162944
J Biol Chem. 2003 Dec 26;278(52):52739-46
14525980
Am J Physiol Lung Cell Mol Physiol. 2002 Aug;283(2):L256-64
12114186
J Biol Chem. 2006 Jul 21;281(29):20140-7
16704971
J Clin Invest. 1982 Sep;70(3):673-83
6896715
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2830-5
18287005
Am J Physiol Lung Cell Mol Physiol. 2005 Dec;289(6):L962-70
16024721
Am Rev Respir Dis. 1989 Feb;139(2):367-9
2913885
Proc Natl Acad Sci U S A. 2001 May 22;98(11):6366-71
11344267
Biochim Biophys Acta. 1984 Sep 12;795(2):238-46
6477944
Biochim Biophys Acta. 1994 Aug 18;1200(3):281-90
8068714
J Bacteriol. 1998 Mar;180(6):1425-30
9515909
J Lipid Res. 1976 May;17(3):281-4
932560
Biochim Biophys Acta. 1983 Jun 2;762(3):398-404
6849986
J Appl Physiol (1985). 1988 Jan;64(1):120-7
3356629
Biochim Biophys Acta. 1979 Mar 29;572(3):452-60
35234
Biochim Biophys Acta. 1985 Jan 9;833(1):93-9
4038460
Am J Respir Crit Care Med. 1996 Jan;153(1):176-84
8542113
Am J Respir Cell Mol Biol. 2004 Feb;30(2):174-83
12896875
J Biol Chem. 2007 Mar 2;282(9):6532-9
17182612
J Lipid Res. 2005 Jun;46(6):1248-56
15772425
Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):88-93
18156367
Pediatr Res. 1980 Mar;14(3):254-8
6892954
Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7794-8
7644495
J Biol Chem. 1959 Mar;234(3):466-8
13641241
Cell Signal. 2003 Jul;15(7):637-65
12742226
Biochim Biophys Acta. 1979 Apr 27;573(1):136-44
582286
N Engl J Med. 2004 Aug 26;351(9):884-92
15329426
J Clin Invest. 1991 Dec;88(6):1976-81
1752956
J Biol Chem. 1997 Jan 24;272(4):2542-50
8999971
Biochim Biophys Acta. 1998 Nov 19;1408(2-3):90-108
9813256
Biochim Biophys Acta. 1986 Oct 3;878(3):301-9
3756197
Expert Opin Investig Drugs. 2006 Jan;15(1):47-58
16370933
Tohoku J Exp Med. 1974 Mar;112(3):241-56
4838064
Neonatology. 2007;91(4):311-7
17575475
J Biol Chem. 2008 Apr 25;283(17):11097-106
18285344
Am J Respir Cell Mol Biol. 2006 Aug;35(2):268-74
16601238
Lipids. 2008 Oct;43(10):895-902
18781350
Biochim Biophys Acta. 1971 Nov 5;248(2):274-81
4331784
Biochim Biophys Acta. 1986 Feb 28;875(3):450-7
3947653
Am J Respir Cell Mol Biol. 2001 Mar;24(3):235-44
11245622
Biochim Biophys Acta. 1976 Sep 27;441(3):443-52
974092
Biochim Biophys Acta. 1984 Jul 26;794(3):392-402
6743672
J Lipid Res. 2009 Aug;50(8):1563-70
19351971
J Lipid Res. 1996 May;37(5):1057-64
8725157
J Clin Invest. 1990 Jul;86(1):1-6
2195058