Activation of SREBP in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity

Background: Lung function is dependent upon the precise regulation of the synthesis, storage, and catabolism of tissue and alveolar lipids. Results: Activation of SREBP (Sterol Response Element Binding Protein) induced lipogenesis in alveolar epithelial cells, causing neutral lipid accumulation, lung inflammation, and tissue remodeling. Conclusions: The accumulation of neutral lipids in type II epithelial cells and alveolar macrophages caused lung inflammation, consistent with findings in lipid storage disorders. Significance: Pulmonary lipotoxicity may contribute to the pathogenesis of lung dysfunction associated with diabetes, obesity, and other metabolic disorders. Genome-wide transcription profiling comparison between doxycycline-exposed SFTPC-rtTAWT/Tg/(tetO)7CMV-CreWT/Tg/Insig1flox/flox/Insig2-/- mice (i.e., Insig1/2∆/∆ ) and Insig1flox/flox/Insig2-/- . Three independent pooled RNA from isolated lung type 2 cells of each genotype were used.

研究背景：肺功能依赖于组织与肺泡脂质的合成、储存及分解代谢的精准调控。
研究结果：固醇调节元件结合蛋白（SREBP，Sterol Response Element Binding Protein）的激活可诱导肺泡上皮细胞发生脂肪生成，进而引发中性脂质蓄积、肺部炎症与组织重塑。
研究结论：II型上皮细胞与肺泡巨噬细胞内的中性脂质蓄积可引发肺部炎症，这一结果与脂质贮积病中的相关发现相符。
研究意义：肺部脂毒性可能参与了糖尿病、肥胖及其他代谢紊乱相关肺功能障碍的发病过程。
全基因组转录谱比较：对经多西环素处理的SFTPC-rtTAWT/Tg/(tetO)7CMV-CreWT/Tg/Insig1flox/flox/Insig2-/-小鼠（即Insig1/2Δ/Δ）与Insig1flox/flox/Insig2-/-小鼠开展全基因组转录谱比较。本实验采用来自两种基因型小鼠分离的肺II型细胞的三份独立混合RNA样本。