title: Lysosomal acid lipase-deficient mice: depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span.
abstract: 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.
authors: Division of Human Genetics, Children's Hospital Research Foundation, Cincinnati, OH 45229, USA. duh0@chmcc.org
authors: H
authors: H
authors: Du
authors: M
authors: M
authors: Heur
authors: M
authors: M
authors: Duanmu
authors: G A
authors: GA
authors: Grabowski
authors: D Y
authors: DY
authors: Hui
authors: D P
authors: DP
authors: Witte
authors: J
authors: J
authors: Mishra
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000375:Aging; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002454:Cell Differentiation; D015217:Cholesterol Ester Storage Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002788:Cholesterol Esters / Q000378:metabolism; D006529:Hepatomegaly / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007333:Insulin Resistance; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008049:Lipase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D008247:Lysosomes / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013163:Splenomegaly / Q000378:metabolism / Q000473:pathology*; D014280:Triglycerides / Q000378:metabolism; D015223:Wolman Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D001786:Blood Glucose; D002788:Cholesterol Esters; D008074:Lipoproteins; D014280:Triglycerides; D008049:Lipase