Lysosomal acid lipase-deficient mice

Depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span

Hong Du, M. Heur, M. Duanmu, G. A. Grabowski, D. Y. Hui, D. P. Witte, J. Mishra

Research output: Contribution to journalArticle

103 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)489-500
Number of pages12
JournalJournal of Lipid Research
Volume42
Issue number4
StatePublished - May 5 2001
Externally publishedYes

Fingerprint

Sterol Esterase
White Adipose Tissue
Brown Adipose Tissue
Liver
Cholesterol Esters
Fats
Tissue
Triglycerides
Lipids
Plasmas
Macrophages
Enzyme activity
Nonesterified Fatty Acids
Metabolism
Hydrolysis
Fatty Acids
Genes
Cholesterol
Insulin
Glucose

Keywords

  • Cholesteryl ester storage disease
  • Fatty liver
  • Wolman disease

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Du, H., Heur, M., Duanmu, M., Grabowski, G. A., Hui, D. Y., Witte, D. P., & Mishra, J. (2001). Lysosomal acid lipase-deficient mice: Depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span. Journal of Lipid Research, 42(4), 489-500.

Lysosomal acid lipase-deficient mice : Depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span. / Du, Hong; Heur, M.; Duanmu, M.; Grabowski, G. A.; Hui, D. Y.; Witte, D. P.; Mishra, J.

In: Journal of Lipid Research, Vol. 42, No. 4, 05.05.2001, p. 489-500.

Research output: Contribution to journalArticle

Du, H, Heur, M, Duanmu, M, Grabowski, GA, Hui, DY, Witte, DP & Mishra, J 2001, 'Lysosomal acid lipase-deficient mice: Depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span', Journal of Lipid Research, vol. 42, no. 4, pp. 489-500.
Du, Hong ; Heur, M. ; Duanmu, M. ; Grabowski, G. A. ; Hui, D. Y. ; Witte, D. P. ; Mishra, J. / Lysosomal acid lipase-deficient mice : Depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span. In: Journal of Lipid Research. 2001 ; Vol. 42, No. 4. pp. 489-500.
@article{aa160a13f5814bbeb03dd37405a32c00,
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.",
keywords = "Cholesteryl ester storage disease, Fatty liver, Wolman disease",
author = "Hong Du and M. Heur and M. Duanmu and Grabowski, {G. A.} and Hui, {D. Y.} and Witte, {D. P.} and J. Mishra",
year = "2001",
month = "5",
day = "5",
language = "English (US)",
volume = "42",
pages = "489--500",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "4",

}

TY - JOUR

T1 - Lysosomal acid lipase-deficient mice

T2 - Depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span

AU - Du, Hong

AU - Heur, M.

AU - Duanmu, M.

AU - Grabowski, G. A.

AU - Hui, D. Y.

AU - Witte, D. P.

AU - Mishra, J.

PY - 2001/5/5

Y1 - 2001/5/5

N2 - 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.

AB - 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.

KW - Cholesteryl ester storage disease

KW - Fatty liver

KW - Wolman disease

UR - http://www.scopus.com/inward/record.url?scp=0035064152&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035064152&partnerID=8YFLogxK

M3 - Article

VL - 42

SP - 489

EP - 500

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 4

ER -