Macrophage-specific expression of human lysosomal acid lipase corrects inflammation and pathogenic phenotypes in lal-/- mice

Cong Yan, Xuemei Lian, Yuan Li, Ying Dai, Amanda White, Yulin Qin, Huimin Li, David A. Hume, Hong Du

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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 (MAL) 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.

Original languageEnglish (US)
Pages (from-to)916-926
Number of pages11
JournalAmerican Journal of Pathology
Volume169
Issue number3
DOIs
StatePublished - Sep 2006

Fingerprint

Macrophages
Inflammation
Phenotype
Doxycycline
Sterol Esterase
Cholesterol Esters
Cytoplasmic and Nuclear Receptors
Lipid Metabolism
Nonesterified Fatty Acids
Triglycerides
Neutrophils
Transcription Factors
Cholesterol
human LIPA protein
Ligands
Gene Expression
Genes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Macrophage-specific expression of human lysosomal acid lipase corrects inflammation and pathogenic phenotypes in lal-/- mice. / Yan, Cong; Lian, Xuemei; Li, Yuan; Dai, Ying; White, Amanda; Qin, Yulin; Li, Huimin; Hume, David A.; Du, Hong.

In: American Journal of Pathology, Vol. 169, No. 3, 09.2006, p. 916-926.

Research output: Contribution to journalArticle

Yan, Cong ; Lian, Xuemei ; Li, Yuan ; Dai, Ying ; White, Amanda ; Qin, Yulin ; Li, Huimin ; Hume, David A. ; Du, Hong. / Macrophage-specific expression of human lysosomal acid lipase corrects inflammation and pathogenic phenotypes in lal-/- mice. In: American Journal of Pathology. 2006 ; Vol. 169, No. 3. pp. 916-926.
@article{88a80a0e1b29480fae809bb89fcf4247,
title = "Macrophage-specific expression of human lysosomal acid lipase corrects inflammation and pathogenic phenotypes in lal-/- mice",
abstract = "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 (MAL) 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.",
author = "Cong Yan and Xuemei Lian and Yuan Li and Ying Dai and Amanda White and Yulin Qin and Huimin Li and Hume, {David A.} and Hong Du",
year = "2006",
month = "9",
doi = "10.2353/ajpath.2006.051327",
language = "English (US)",
volume = "169",
pages = "916--926",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - Macrophage-specific expression of human lysosomal acid lipase corrects inflammation and pathogenic phenotypes in lal-/- mice

AU - Yan, Cong

AU - Lian, Xuemei

AU - Li, Yuan

AU - Dai, Ying

AU - White, Amanda

AU - Qin, Yulin

AU - Li, Huimin

AU - Hume, David A.

AU - Du, Hong

PY - 2006/9

Y1 - 2006/9

N2 - 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 (MAL) 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.

AB - 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 (MAL) 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.

UR - http://www.scopus.com/inward/record.url?scp=33748782801&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33748782801&partnerID=8YFLogxK

U2 - 10.2353/ajpath.2006.051327

DO - 10.2353/ajpath.2006.051327

M3 - Article

C2 - 16936266

AN - SCOPUS:33748782801

VL - 169

SP - 916

EP - 926

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 3

ER -