Human Molecular Genetics, Vol 7, 1347-1354, Copyright © 1998 by Oxford University Press
H Du, M Duanmu, D Witte and GA Grabowski
Lysosomal acid lipase (LAL) is essential for the hydrolysis of the
triglycerides and cholesteryl esters in lysosomes. Its deficiency produces
two phenotypes, a severe infantile-onset variant, Wolman disease (WD), and
a later onset variant, cholesteryl ester storage disease (CESD). A mouse
model with a LAL null mutation was produced by targeting disruption of the
mouse gene. Homozygote knockout mice (lal - /lal-) produce no LAL mRNA,
protein or enzyme activity. The lal-/lal- mice are born in Mendelian
ratios, are normal appearing at birth, and follow normal development into
adulthood. However, massive accumulation of triglycerides and cholesteryl
esters occurs in several organs. By 21 days, the liver develops a
yellow-orange color and is approximately 1.5- 2.0x larger than normal. The
accumulated cholesteryl esters and triglycerides are approximately 30-fold
greater than normal. The lal+/lal- mice have approximately 50% of normal
LAL activity and do not show lipid accumulation. Male and female lal-/lal-
mice are fertile and can be bred to produce progeny. This mouse model is a
phenotypic model of human CESD, and a biochemical and histopathologic mimic
of human WD. The lal-/lal- mice provide a model to determine the role of
LAL in lipid metabolism and the pathogenesis of its deficiency states.
ARTICLES
Targeted disruption of the mouse lysosomal acid lipase gene: long-term survival with massive cholesteryl ester and triglyceride storage
Division of Human Genetics, Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Xie, S. D. Turley, and J. M. Dietschy ABCA1 plays no role in the centripetal movement of cholesterol from peripheral tissues to the liver and intestine in the mouse J. Lipid Res., July 1, 2009; 50(7): 1316 - 1329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Qu, H. Du, D. S. Wilkes, and C. Yan Critical Roles of Lysosomal Acid Lipase in T Cell Development and Function Am. J. Pathol., March 1, 2009; 174(3): 944 - 956. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Liu, S. D. Turley, D. K. Burns, A. M. Miller, J. J. Repa, and J. M. Dietschy From the Cover: Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1-/- mouse PNAS, February 17, 2009; 106(7): 2377 - 2382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Qu, H. Du, Y. Li, and C. Yan Myeloid-Specific Expression of Api6/AIM/Sp{alpha} Induces Systemic Inflammation and Adenocarcinoma in the Lung J. Immunol., February 1, 2009; 182(3): 1648 - 1659. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Du, T. L. Cameron, S. J. Garger, G. P. Pogue, L. A. Hamm, E. White, K. M. Hanley, and G. A. Grabowski Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice J. Lipid Res., August 1, 2008; 49(8): 1646 - 1657. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Woloszynek, T. Coleman, C. F. Semenkovich, and M. S. Sands Lysosomal Dysfunction Results in Altered Energy Balance J. Biol. Chem., December 7, 2007; 282(49): 35765 - 35771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Liu, C. Xie, J. A. Richardson, S. D. Turley, and J. M. Dietschy Receptor-mediated and bulk-phase endocytosis cause macrophage and cholesterol accumulation in Niemann-Pick C disease J. Lipid Res., August 1, 2007; 48(8): 1710 - 1723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. P. Beltroy, B. Liu, J. M. Dietschy, and S. D. Turley Lysosomal unesterified cholesterol content correlates with liver cell death in murine Niemann-Pick type C disease J. Lipid Res., April 1, 2007; 48(4): 869 - 881. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Ikonen Mechanisms for cellular cholesterol transport: defects and human disease. Physiol Rev, October 1, 2006; 86(4): 1237 - 1261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Yan, X. Lian, Y. Li, Y. Dai, A. White, Y. Qin, H. Li, D. A. Hume, and H. Du Macrophage-Specific Expression of Human Lysosomal Acid Lipase Corrects Inflammation and Pathogenic Phenotypes in lal-/- Mice Am. J. Pathol., September 1, 2006; 169(3): 916 - 926. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Zschenker, T. Illies, and D. Ameis Overexpression of lysosomal Acid lipase and other proteins in atherosclerosis. J. Biochem., July 1, 2006; 140(1): 23 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Zschenker, C. Bahr, U.-F. Hess, and D. Ameis Systematic Mutagenesis of Potential Glycosylation Sites of Lysosomal Acid Lipase J. Biochem., March 1, 2005; 137(3): 387 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Du, B. J. Dardzinski, K. J. O'Brien, and L. F. Donnelly MRI of Fat Distribution in a Mouse Model of Lysosomal Acid Lipase Deficiency Am. J. Roentgenol., February 1, 2005; 184(2): 658 - 662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Yan and H. Du Alveolus formation: what have we learned from genetic studies? J Appl Physiol, October 1, 2004; 97(4): 1543 - 1548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Lian, C. Yan, L. Yang, Y. Xu, and H. Du Lysosomal acid lipase deficiency causes respiratory inflammation and destruction in the lung Am J Physiol Lung Cell Mol Physiol, April 1, 2004; 286(4): L801 - L807. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Du, S. Schiavi, N. Wan, M. Levine, D. P. Witte, and G. A. Grabowski Reduction of Atherosclerotic Plaques by Lysosomal Acid Lipase Supplementation Arterioscler Thromb Vasc Biol, January 1, 2004; 24(1): 147 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Du, S. Schiavi, M. Levine, J. Mishra, M. Heur, and G. A. Grabowski Enzyme therapy for lysosomal acid lipase deficiency in the mouse Hum. Mol. Genet., August 1, 2001; 10(16): 1639 - 1648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Du, M. Heur, M. Duanmu, G. A. Grabowski, D. Y. Hui, D. P. Witte, and J. Mishra Lysosomal acid lipase-deficient mice: depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span J. Lipid Res., April 1, 2001; 42(4): 489 - 500. [Abstract] [Full Text]
|
|
|
|
 |
|
 W. Wang, W. Li, Y. Ikeda, J.-I. Miyagawa, M. Taniguchi, E. Miyoshi, Y. Sheng, A. Ekuni, J. H. Ko, Y. Yamamoto, et al. Ectopic expression of {{alpha}}1,6 fucosyltransferase in mice causes steatosis in the liver and kidney accompanied by a modification of lysosomal acid lipase Glycobiology, February 1, 2001; 11(2): 165 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Buton, Z. Mamdouh, R. Ghosh, H. Du, G. Kuriakose, N. Beatini, G. A. Grabowski, F. R. Maxfield, and I. Tabas Unique Cellular Events Occurring during the Initial Interaction of Macrophages with Matrix-retained or Methylated Aggregated Low Density Lipoprotein (LDL). PROLONGED CELL-SURFACE CONTACT DURING WHICH LDL-CHOLESTERYL ESTER HYDROLYSIS EXCEEDS LDL PROTEIN DEGRADATION J. Biol. Chem., November 5, 1999; 274(45): 32112 - 32121. [Abstract] [Full Text] [PDF]
|
|