Journal Article

Targeted Disruption of the Mouse Lysosomal Acid Lipase Gene: Long-Term Survival with Massive Cholesteryl Ester and Triglyceride Storage

Hong Du, Ming Duanmu, David Witte and Gregory A. Grabowski

in Human Molecular Genetics

Volume 7, issue 9, pages 1347-1354
Published in print September 1998 | ISSN: 0964-6906
Published online September 1998 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/7.9.1347
Targeted Disruption of the Mouse Lysosomal Acid Lipase Gene: Long-Term Survival with Massive Cholesteryl Ester and Triglyceride Storage

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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 (lalllal) produce no LAL mRNA, protein or enzyme activity. The lalllal 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 ∼1.5–2.0× larger than normal. The accumulated cholesteryl esters and triglycerides are ∼30-fold greater than normal. The lal+llal mice have ∼50% of normal LAL activity and do not show lipid accumulation. Male and female lalllal 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+llal mice provide a model to determine the role of LAL in lipid metabolism and the pathogenesis of its deficiency states.

Journal Article.  5477 words.  Illustrated.

Subjects: Genetics and Genomics

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