Deletion of Scap in Alveolar Type II Cells Influences Lung Lipid Homeostasis and Identifies a Compensatory Role for Pulmonary Lipofibroblasts

Abstract

Pulmonary surfactant consists of lipids and associated proteins that reduce surface tension at the air-liquid interface. Surfactant is required for adaptation to air breathing after birth. Lack of surfactant in preterm infants causes infantile respiratory distress syndrome and acute respiratory distress syndrome in older individuals. Likewise, mutations in genes regulating surfactant homeostasis, including SFTPB, SFTPC, and ABCA3, disrupt surfactant homeostasis causing fatal respiratory distress or chronic lung disease (1, 2). Although various lipids play a critical role in surfactant function, transcriptional mechanisms regulating surfactant homeostasis in the respiratory epithelium remain poorly understood.In other tissues, transcriptional mechanisms regulating lipid synthesis are known to be dependent on a number of transcription factors, including CCAAT/enhancer-binding protein (C/EBP) 2 isoforms, liver X receptor, peroxisome proliferatoractivated receptors (PPARs), and sterol regulatory elementbinding proteins (SREBPs) (3-6). Although transcriptional networks regulating lipid homeostasis have been extensively studied in other cell types, including hepatocytes and adipocytes, less is known regarding transcriptional control of lipid homeostasis in the respiratory epithelium. SREBP-1c, C/EBP␣, and C/EBP␦ regulate lipogenic enzymes and transport proteins in the lung (7-11). C/EBP isoforms and SREBP-1c mRNAs are increased in the fetal rat lung during late gestation in association with increased expression of surfactant proteins (A, B, C, and D) (1). Induction of proteins regulating lipid synthesis and surfactant proteins occurs during perinatal lung maturation and is required for respiratory function at birth.Three SREBP isoforms, SREBP-1a, SREBP-1c, and SREBP-2, are synthesized as inactive precursors that are inserted into the membranes of the endoplasmic reticulum (ER), where they bind to SREBP cleavage-activating protein (SCAP). In response to cholesterol depletion, SCAP transports the SREBPs from the endoplasmic reticulum to the Golgi, where the NH 2 -terminal domain of SREBP, the active form of the transcription factor, is released by proteolytic cleavage by two proteases, S2P and S2P, allowing the active SREBP to enter the nucleus where it binds and activates transcription of target genes. SREBPs regulate many aspects of lipid biosynthesis; SREBP-1a and, particularly, SREBP-1c are relatively selective for the regulation of fatty acid synthesis, whereas SREBP-2 is a more potent activator of cholesterol synthesis (3, 12). * This work was supported, in whole or in part, by National Institutes of Health Grants HL-85610 and HL-90156 (to J. A. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 Although SREBP-1c regulates a number o...

Chronic Alcohol Ingestion in Rats Alters Lung Metabolism, Promotes Lipid Accumulation, and Impairs Alveolar Macrophage Functions

“…Recent evidence indicates that Srebf1 plays an important role in regulating TG levels in the lung (33). Mice with deletions of insulin-induced gene 1 and insulin-induced gene 2, both of which encode for proteins that inhibit Srebf, displayed enhanced Srebf1 function associated with marked accumulation of TGs in both AEII cells and AMs (32,34,35). Conversely, deletion of the sterolregulatory-element-binding cleavageassociated protein, which is required for Srebf activation, was associated with a nonsignificant decrease in TG levels in AEII cells.…”

Thy-1 Signals through PPARγ to Promote Lipofibroblast Differentiation in the Developing Lung

“…The total lung lipid content of Thy-1 2/2 mice on PND14 is less than for WT mice ( Figure E2F). Lipid droplets were not present in alveolar Type II cells, as seen in other models of dysregulated pulmonary fibroblast lipid metabolism ( Figure E3) (28). The deletion of Thy-1 in the Thy-1 2/2 mouse is not pulmonary fibroblast-specific, and in vitro findings from isolated fibroblasts may not represent in vivo conditions.…”

EMC3 coordinates surfactant protein and lipid homeostasis required for respiration

“…This change could be due to the transcriptional regulation of active UPR in response to the accumulation of unfolded/misfolded proteins in Emc3-cKO AT2 cells. As a master transcription regulator of cellular lipogenesis, suppression of SREBP1/2 may mediate alterations in surfactant lipid homeostasis (22,23). In Emc3-cKO AT2 cells, lipid concentrations were markedly decreased (Supplemental Table 3).…”