Macrophage-specific expression of human lysosomal acid lipase corrects inflammation and pathogenic phenotypes in lal-/- mice.
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 macrophages 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-fms 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.
Yan
Cong
C
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, and Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA. coyan@iupui.edu
Lian
Xuemei
X
Li
Yuan
Y
Dai
Ying
Y
White
Amanda
A
Qin
Yulin
Y
Li
Huimin
H
Hume
David A
DA
Du
Hong
H
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002788:Cholesterol Esters / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008247:Lysosomes / Q000201:enzymology / Q000235:genetics; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D002787:Sterol Esterase / Q000096:biosynthesis* / Q000235:genetics
D000900:Anti-Bacterial Agents; D002788:Cholesterol Esters; C503451:LIPA protein, human; D002787:Sterol Esterase; D004318:Doxycycline