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PMID: 16936266 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

The American journal of pathology ·Vol. 169 ·No. 3 ·2006-09-00 ·Pages 916-26

Yan C, Lian X, Li Y, Dai Y, White A, Qin Y, Li H, Hume DA, Du H

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 (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.

MeSH Terms
Animals Anti-Bacterial Agents/pharmacology Cholesterol Esters/metabolism Doxycycline/pharmacology Gene Expression Regulation/drug effects,genetics Humans Inflammation/genetics,metabolism,pathology Lipid Metabolism/drug effects,genetics Lysosomes/enzymology,genetics Macrophages/enzymology,pathology Mice Mice, Knockout Neutrophils/metabolism,pathology Organ Specificity/drug effects,genetics Sterol Esterase/biosynthesis,genetics
Chemicals
Anti-Bacterial Agents Cholesterol Esters LIPA protein, human Sterol Esterase Doxycycline
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Yan Cong
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. [email protected]
Lian Xuemei
Li Yuan
Dai Ying
White Amanda
Qin Yulin
Li Huimin
Hume David A
Du Hong
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.2353/ajpath.2006.051327
Email
[email protected]
Published
2006-09-00
Pages
916-26
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1698822
Subset
IM
Grants
NHLBI NIH HHS · R01 HL061803 · United States
NHLBI NIH HHS · R01 HL067862 · United States
NHLBI NIH HHS · HL-061803 · United States
NHLBI NIH HHS · HL-067862 · United States
External Links
PubMed source DOI: 10.2353/ajpath.2006.051327 PMC Full Text View journal details
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