Macrophage-specific expression of human lysosomal acid lipase corrects inflammation and pathogenic phenotypes in lal-/- mice
Macrophage-specific expression of human lysosomal acid lipase corrects inflammation and pathogenic phenotypes in lal-/- mice
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DOI：
10.2353/ajpath.2006.051327
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发表时间：
2006-09-01
影响因子：
6
通讯作者：
Du, Hong
中科院分区：
文献类型：
--
作者：
Yan, Cong;Lian, Xuemei;Du, Hong
溶酶体酸性脂肪酶(LAL)能分解胆固醇酯和甘油三酯，在细胞内生成游离脂肪酸和胆固醇。这些化合物的下游代谢产物作为核受体和转录因子的激素配体。小鼠Lal基因的遗传消融导致巨噬细胞畸形，并在多个器官中引发炎症引发的多种致病表型。为了研究巨噬菌体与LAL(-/-)致病表型的关系，建立了巨噬细胞特异性强力霉素诱导的转基因系统，在LAL(-/-)遗传背景下，在7.2kb c-FINS启动子/内含子2调控序列的控制下，诱导人LAL(-/-)的表达。多西环素诱导巨噬细胞表达hlal可显著改善异常基因表达、炎性细胞(中性粒细胞)渗入和多器官病变。这些研究有力地支持了巨噬细胞的中性脂代谢在器官炎症和发病机制中的作用。
Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in the cell. The downstream metabolites of these compounds serve as hormonal ligands for nuclear receptors and transcription factors. Genetic ablation of the lal gene in the mouse caused malformation of macrophages and inflammation-triggered multiple pathogenic phenotypes in multiple organs. To assess the relationship between macro phages and lal(-/-) pathogenic phenotypes, a macrophage-specific doxycycline-inducible transgenic system was generated to induce human LAL (hLAL) expression in the lal(-/-) genetic background under control of the 7.2-kb c-fins promoter/intron2 regulatory sequence. Doxycycline-induced hLAL expression in macrophages significantly ameliorated aberrant gene expression, inflammatory cell (neutrophil) influx, and pathogenesis in multiple organs. These studies strongly support that neutral lipid metabolism in macrophages contributes to organ inflammation and pathogenesis.