Cholesteryl ester storage disease (CESD) results from loss-of-function mutations in LIPA, the gene that encodes
lysosomal acid lipase (LAL).
Hepatomegaly and deposition of esterified
cholesterol (EC) in multiple organs ensue. The present studies quantitated rates of synthesis, absorption, and disposition of
cholesterol, and whole body
cholesterol pool size in a mouse model of CESD. In 50-day-old lal(-/-) and matching lal(+/+) mice fed a low-
cholesterol diet, whole animal
cholesterol content equalled 210 and 50 mg, respectively, indicating that since birth the lal(-/-) mice sequestered
cholesterol at an average rate of 3.2 mg·day(-1)·animal(-1). The proportion of the body
sterol pool contained in the liver of the lal(-/-) mice was 64 vs. 6.3% in their lal(+/+) controls. EC concentrations in the liver, spleen, small intestine, and lungs of the lal(-/-) mice were elevated 100-, 35-, 15-, and 6-fold, respectively. In the lal(-/-) mice, whole liver
cholesterol synthesis increased 10.2-fold, resulting in a 3.2-fold greater rate of whole animal
sterol synthesis compared with their lal(+/+) controls. The rate of
cholesterol synthesis in the lal(-/-) mice exceeded that in the lal(+/+) controls by 3.7 mg·day(-1)·animal(-1). Fractional
cholesterol absorption and fecal
bile acid excretion were unchanged in the lal(-/-) mice, but their rate of neutral
sterol excretion was 59% higher than in their lal(+/+) controls. Thus, in this model, the continual expansion of the body
sterol pool is driven by the synthesis of excess
cholesterol, primarily in the liver. Despite the severity of their disease, the median life span of the lal(-/-) mice was 355 days.