Neutral lipids and peroxisome proliferator-activated receptor-{gamma} control pulmonary gene expression and inflammation-triggered pathogenesis in lysosomal acid lipase knockout mice.
The functional roles of neutral lipids in the lung are poorly understood. However, blocking cholesteryl ester and triglyceride metabolism in lysosomal acid lipase gene knockout mice (lal-/-) results in severe pathogenic phenotypes in the lung, including massive neutrophil infiltration, foamy macrophage accumulation, unwanted cell growth, and emphysema. To elucidate the mechanism underlining these pathologies, we performed Affymetrix GeneChip microarray analysis of 1-, 3-, and 6-month-old mice and identified aberrant gene expression that progressed with age. Among changed genes, matrix metalloproteinase (MMP)-12, apoptosis inhibitor 6 (Api-6), erythroblast transformation-specific domain (Ets) transcription factor family member Spi-C, and oncogene MafB were increased 100-, 70-, 40-, and 10-fold, respectively, in lal-/- lungs versus the wild-type lungs. The pathogenic increases of these molecules occurred primarily in alveolar type II epithelial cells. Transcriptional activities of the MMP-12 and Api-6 promoters were stimulated by Spi-C or MafB in respiratory epithelial cells. Treatment with 9-hydroxyoctadecanoic acids and ciglitazone significantly rescued lal-/- pulmonary inflammation and aberrant gene expression. In addition, both compounds as well as peroxisome proliferator-activated receptor gamma inhibited MMP-12 and Api-6 promoter activities. These data suggest that inflammation-triggered cell growth and emphysema during lysosomal acid lipase deficiency are partially caused by peroxisome proliferator-activated receptor-gamma inactivation.
Lian
Xuemei
X
Division of Pulmonary Biology, or Hong Du, Ph.D., Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Yan
Cong
C
Qin
Yulin
Y
Knox
Lana
L
Li
Tingyu
T
Du
Hong
H
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004268:DNA-Binding Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007249:Inflammation / Q000150:complications* / Q000378:metabolism; D050356:Lipid Metabolism; D008168:Lung / Q000378:metabolism*; D008171:Lung Diseases / Q000209:etiology*; D051258:MafB Transcription Factor; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D051116:Receptors, Scavenger; D020545:Respiratory Mucosa / Q000378:metabolism; D002787:Sterol Esterase / Q000172:deficiency* / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D051017:Apoptosis Regulatory Proteins; C117272:Cd5l protein, mouse; D004268:DNA-Binding Proteins; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D015513:Oncogene Proteins; D047495:PPAR gamma; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C423918:Spic protein, mouse; D014157:Transcription Factors; D002787:Sterol Esterase; C505054:lysosomal acid lipase, mouse; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12