Deletion of Scap in alveolar type II cells influences lung lipid homeostasis and identifies a compensatory role for pulmonary lipofibroblasts.
Pulmonary function after birth is dependent upon surfactant lipids that reduce surface tension in the alveoli. The sterol-responsive element-binding proteins (SREBPs) are transcription factors regulating expression of genes controlling lipid homeostasis in many tissues. To identify the role of SREBPs in the lung, we conditionally deleted the SREBP cleavage-activating protein gene, Scap, in respiratory epithelial cells (ScapDelta/Delta) in vivo. Prior to birth (E18.5), deletion of Scap decreased the expression of both SREBPs and a number of genes regulating fatty acid and cholesterol metabolism. Nevertheless, ScapDelta/Delta mice survived postnatally, surfactant and lung tissue lipids being substantially normalized in adult ScapDelta/Delta mice. Although phospholipid synthesis was decreased in type II cells from adult ScapDelta/Delta mice, lipid storage, synthesis, and transfer by lung lipofibroblasts were increased. mRNA microarray data indicated that SCAP influenced two major gene networks, one regulating lipid metabolism and the other stress-related responses. Deletion of the SCAP/SREBP pathway in respiratory epithelial cells altered lung lipid homeostasis and induced compensatory lipid accumulation and synthesis in lung lipofibroblasts.
Besnard
Valérie
V
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA.
Wert
Susan E
SE
Stahlman
Mildred T
MT
Postle
Anthony D
AD
Xu
Yan
Y
Ikegami
Machiko
M
Whitsett
Jeffrey A
JA
D000818:Animals; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010743:Phospholipids; C102196:SREBP cleavage-activating protein; D051779:Sterol Regulatory Element Binding Proteins