Metabolism and fate of neutral lipids of fetal lung fibroblast origin

Torday, John S.; Hua, Jinping; Slavin, Richard E.

doi:10.1016/0005-2760(94)00184-z

Cited by 104 publications

(106 citation statements)

References 24 publications

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“…Magra et al (48) have proposed that ADFP may be involved in the transfer of lipid from lipofibroblasts to lung alveolar type II epithelial cells for the production of surfactant phospholipid. This study provides further support for a model in which lipid fibroblasts interact closely with type II epithelial cells to modulate lipid substrate supply needed for surfactant synthesis and support the role of this interaction in perinatal lung development as proposed by Torday et al (37)(38)(39). One additional implication of these observations is that the decreased PC synthesis in isolated adult type II alveolar cells must be a consequence of their inadequate ability to synthesize fatty acids de novo, rather than being due to fundamental abnormalities in either the CDP:choline pathway for PC synthesis or in mechanisms regulating surfactant packaging in lamellar bodies.…”

Section: Discussionsupporting

confidence: 84%

“…⌬/⌬ Mice-Lipofibroblasts present numerous lipid droplets containing triglycerides and other lipids that can be transferred to the majority of alveolar type II cells and used in the synthesis of pulmonary surfactant (37)(38)(39). In general, lung morphology in adult Scap ⌬/⌬ mice was normal; however, focal lobar and panacinar emphysema was noted in ϳ30% of the mice (data not shown).…”

Section: Identification Of a Compensatory Pathway In The Lipofibroblamentioning

confidence: 99%

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

Besnard

Wert

Stahlman

et al. 2009

Journal of Biological Chemistry

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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...

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Section: Discussionsupporting

confidence: 84%

Section: Identification Of a Compensatory Pathway In The Lipofibroblamentioning

confidence: 99%

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

Besnard

Wert

Stahlman

et al. 2009

Journal of Biological Chemistry

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“…Moreover, Brody's laboratory had shown that the developing lung fibroblast acquired an adipocyte-like phenotype (15), termed the lipidladen fibroblast, leaving open the question as to whether these cells might be a source of lipid substrate for surfactant synthesis by the alveolar type II cell. We discovered that coculture of the lipid-laden fibroblasts with type II cells resulted in the trafficking of the lipid from the fibroblast to the type II cell and its highly enriched incorporation into surfactant phospholipids, particularly when treated with glucocorticoids, suggesting a specific, regulated mechanism for neutral lipid trafficking (16). Interestingly, the fibroblasts took up the neutral lipid, but did not release it unless they were in the presence of type II cells; conversely, the type II cells were unable to take up neutral lipid.…”

Section: Epithelial-mesenchymal Interactions That Establish Alveolar mentioning

confidence: 99%

Developmental Cell/Molecular Biologic Approach to the Etiology and Treatment of Bronchopulmonary Dysplasia

Torday

Rehan

2007

Pediatr Res

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ABSTRACT:We have taken a basic biologic approach to elucidate the pathophysiology of bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, based on cell/molecular mechanisms of physiologic lung development. Stretch coordinates parathyroid hormone-related protein (PTHrP) signaling between the alveolar type II cell and the mesoderm to coordinately up-regulate key genes for the homeostatic fibroblast phenotype-including peroxisome proliferator activated receptor gamma (PPAR␥), adipocyte differentiation related protein (ADRP), and leptin-and the retrograde stimulation of type II cell surfactant synthesis by leptin. Each of these paracrine interactions requires cell-specific receptors on adjacent cells derived from the mesoderm or endoderm, respectively, to serially up-regulate the signaling pathways between and within each cell-type. It is this functional compartmentation that is key to understanding how specific agonists and antagonists can predictably affect this mechanism of alveolar homeostasis. Using a wide variety of pathophysiologic insults associated with BPD-barotrauma, oxotrauma, and infection, we have found that there are type II cell and/or fibroblast cell/molecular effects generated by these insults, which can lead to the BPD phenotype. We have exploited these cell-specific mechanisms to effectively prevent and treat lung injuries using PPAR␥ agonists to sustain this signaling pathway. It is critically important to judiciously select physiologically and developmentally relevant interventions when treating the preterm neonate. (Pediatr Res 62: 2-7, 2007) I n the current reductionist era of genomics, proteomics, metabolomics, etc., it is important to bear in mind that genes can only be understood functionally within their biologic context (1). We cannot decipher complex diseases merely by identifying the genes that are associated with them without understanding how those genes relate to their pathophysiologic phenotypes. In this spirit, we will review a series of studies performed in our laboratory designed to determine the cell/molecular etiology and treatment of chronic lung disease based on an integrated model of lung development, homeostasis, and disease (2).Lung morphogenesis and repair are characterized by a complex sequence of cell-cell interactions of endodermal and mesodermal origins, which has evolved an alveolar structure that can effectively exchange gases between the circulation and the alveolar space (3). By determining the spatio-temporal nature of this process, we can gain insights into the pathophysiology of a broad spectrum of chronic lung diseases caused by both intrinsic and extrinsic factors, bearing in mind that they descriptively funnel into just a few pathologiesepithelial, interstitial, and/or vascular.The global mechanisms that mediate mesenchymalepithelial interactions and the plasticity of mesenchymal cells in normal lung development and remodeling provide a functional genomic model that offers insights to the cell/molecular basis for lung homeostasis (4 -6...

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“…The plasticity of the alveolar interstitium derives from both the fibroblasts, which are not terminally differentiated (6), and the epithelial cells, which differentiate into type II cells (7) and can differentiate into type-I cells (8). These phenotypes are affected by various extrinsic factors, including stretch (9), endocrine hormones (10,11), cytokines (3), oxygen (12,13), nutrition (14), nicotine (15), and inflammation (16).…”

mentioning

confidence: 99%

Up-Regulation of Fetal Rat Lung Parathyroid Hormone-Related Protein Gene Regulatory Network Down-Regulates the Sonic Hedgehog/Wnt/βcatenin Gene Regulatory Network

Torday

Rehan

2006

Pediatr Res

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Lung development depends on endodermal Sonic Hedgehog (Shh) signaling to mesodermal Wingless/int/beta catenin (Wnt/␤catenin), followed by parathyroid hormone-related protein (PTHrP) signaling from endoderm to mesoderm. Fluid distension of fetal rat lung explants up-regulates PTHrP signaling and downregulates Shh/Wnt/␤catenin signaling, marked by decreases in Patched, Gli, Frizzled, and Dishevelled, inducing fibroblast triglyceride uptake, type II cell saturated phosphatidylcholine, and surfactant protein-B expression. Bumetanide, which inhibits fluid distension, blocked down-regulation of the Shh/Wnt/␤catenin pathway and up-regulation of the PTHrP pathway, whereas PTHrP (1-34, 5 ϫ 10 Ϫ7 M) treatment overcame bumetanide inhibition, and the PTHrP receptor antagonist PTHrP (7-34) amide (5 ϫ 10 Ϫ6 M) mimicked bumetanide, indicating that PTHrP signaling mediates fluid distension-induced alveolar differentiation. Fetal rat lung explant automaturation was characterized by decreased Wnt/␤catenin signaling and increased PTHrP/PTHrP receptor signaling, up-regulating fibroblastspecific adipocyte differentiation related protein (ADRP) and peroxisome proliferator-activated receptor gamma. Wnt/␤catenin agonists (LiCl or SB415268) maintained Shh/Wnt/␤catenin signaling, blocking spontaneous up-regulation of the PTHrP pathway, whereas PTHrP or cAMP down-regulated Shh/Wnt/␤catenin signaling and stimulated PTHrP signaling for fibroblast and type II cell differentiation. This is the first evidence that alveolar fluid distension is an organizing principle for PTHrP signaling down-regulation of the Shh/Wnt/␤catenin pathway. (Pediatr Res 60: 382-388, 2006)

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Metabolism and fate of neutral lipids of fetal lung fibroblast origin

Cited by 104 publications

References 24 publications

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

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

Developmental Cell/Molecular Biologic Approach to the Etiology and Treatment of Bronchopulmonary Dysplasia

Up-Regulation of Fetal Rat Lung Parathyroid Hormone-Related Protein Gene Regulatory Network Down-Regulates the Sonic Hedgehog/Wnt/βcatenin Gene Regulatory Network

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