Epithelial SCAP/INSIG/SREBP signaling regulates multiple biological processes during perinatal lung maturation.

Pulmonary surfactant is required for lung function at birth and throughout postnatal life. Defects in the surfactant system are associated with common pulmonary disorders including neonatal respiratory distress syndrome and acute respiratory distress syndrome in children and adults. Lipogenesis is essential for the synthesis of pulmonary surfactant by type II epithelial cells lining the alveoli. This study sought to identify the role of pulmonary epithelial SREBP, a transcriptional regulator of cellular lipid homeostasis, during a critical time period of perinatal lung maturation in the mouse. Genome wide mRNA expression profiling of lung tissue from transgenic mice with epithelial-specific deletions of Scap (ScapΔ/Δ, resulting in inactivation of SREBP signaling) or Insig1 and Insig2 (Insig1/2 Δ/Δ, resulting in activation of SREBP signaling) was assessed. Differentially expressed genes responding to SREBP perturbations were identified and subjected to functional enrichment analysis, pathway mapping and literature mining to predict upstream regulators and transcriptional networks regulating surfactant lipid homeostasis. Through comprehensive data analysis and integration, time dependent effects of epithelial SCAP/INSIG/SREBP deletion and defined SCAP/INSIG/SREBP-associated genes, bioprocesses and downstream pathways were identified. SREBP signaling influences epithelial development, cell death and cell proliferation at E17.5, while primarily influencing surfactant physiology, lipid/sterol synthesis, and phospholipid transport after birth. SREBP signaling integrated with the Wnt/β-catenin and glucocorticoid receptor signaling pathways during perinatal lung maturation. SREBP regulates perinatal lung lipogenesis and maturation through multiple mechanisms by interactions with distinct sets of regulatory partners.

肺表面活性物质在出生时及出生后的整个生命过程中对肺功能都是必需的。表面活性物质系统的缺陷与常见的肺部疾病有关，包括新生儿呼吸窘迫综合征以及儿童和成人的急性呼吸窘迫综合征。脂肪生成对于肺泡上皮Ⅱ型细胞合成肺表面活性物质至关重要。本研究旨在确定肺上皮SREBP（一种细胞脂质内稳态的转录调节因子）在小鼠围产期肺成熟的关键时期所起的作用。对具有上皮特异性Scap缺失（ScapΔ/Δ，导致SREBP信号失活）或Insig1和Insig2缺失（Insig1/2 Δ/Δ，导致SREBP信号激活）的转基因小鼠肺组织进行全基因组mRNA表达谱分析。识别对SREBP扰动有反应的差异表达基因，并对其进行功能富集分析、通路映射和文献挖掘，以预测调节表面活性物质脂质内稳态的上游调节因子和转录网络。通过全面的数据分析和整合，确定了上皮SCAP/INSIG/SREBP缺失的时间依赖性效应以及明确的与SCAP/INSIG/SREBP相关的基因、生物过程和下游通路。SREBP信号在E17.5影响上皮发育、细胞死亡和细胞增殖，而在出生后主要影响表面活性物质生理、脂质/固醇合成以及磷脂转运。在围产期肺成熟过程中，SREBP信号与Wnt/β - 连环蛋白和糖皮质激素受体信号通路整合。SREBP通过与不同组的调节伙伴相互作用，以多种机制调节围产期肺脂肪生成和成熟。