出版社：American Society for Biochemistry and Molecular Biology
摘要：Lysosomal acid lipase (LAL) is essential for the hydrolysis of triglycerides (TG) and cholesteryl esters (CE) in lysosomes. A mouse model created by gene targeting produces no LAL mRNA, protein, or enzyme activity. The lal −/− mice appear normal at birth, survive into adulthood, and are fertile. Massive storage of TG and CE is observed in adult liver, adrenal glands, and small intestine. The age-dependent tissue and gross progression in this mouse model are detailed here. Although lal −/− mice can be bred to give homozygous litters, they die at ages of 7 to 8 months. The lal −/− mice develop enlargement of a single mesenteric lymph node that is full of stored lipids. At 6–8 months of age, the lal −/− mice have completely absent inguinal, interscapular, and retroperitoneal white adipose tissue. In addition, brown adipose tissue is progressively lost. The plasma free fatty acid levels are significantly higher in lal −/− mice than age-matched lal +/+ mice, and plasma insulin levels were more elevated upon glucose challenge. Energy intake was also higher in lal −/− male mice, although age-matched body weights were not significantly altered from age-matched lal +/+ mice. Early in the disease course, hepatocytes are the main storage cell in the liver; by 3–8 months, the lipid-stored Kupffer cells progressively fill the liver. The involvement of macrophages throughout the body of lal −/− mice provide evidence for a critical nonappreciated role of LAL in cellular cholesterol and fatty acid metabolism, adipocyte differentiation, and fat mobilization. —Du, H., 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. 2001. 42: 489–500.
