Lysosomal acid lipase-deficient mice: depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span

Lysosomal acid lipase (LAL) is essential for the hydrolysis of triglyceride s (TG) and cholesteryl esters (CE) in lysosomes, A mouse model created by g ene targeting produces no LAL mRNA, protein, or enzyme activity. The lal-/- mice appear normal at birth, survive into adulthood, and are fertile, Mass ive storage of TG and CE is observed in adult liver, adrenal glands, and sm all intestine, The age-dependent tissue and gross progression in this mouse model are detailed here. Although lal-/- mice can be bred to give homozygo us litters, they die at ages of 7 to 8 months, The lal-/- mice develop enla rgement 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, inters capular, and retroperitoneal white adipose tissue. In addition, brown adipo se tissue is progressively lost, The plasma free fatty acid levels are sign ificantly higher in lal-/- mice than age-matched lal+/+ mice, and plasma in sulin levels were more elevated upon glucose challenge, Energy intake was a lso higher in lal-/- male mice, although age-matched body weights were not significantly altered from age-matched lal+/+ mice, Early in the disease co urse, hepatocytes are the main storage cell in the liver; by 3-8 months, th e lipid-stored Kupffer cells progressively fill the liver. The involvement of macrophages throughout the body of lal-/- mice provide evidence for a cr itical nonappreciated role of LAL in cellular cholesterol and fatty acid me tabolism, adipocyte differentiation, and fat mobilization.