Lysosomal acid lipase (LAL), encoded by the gene LIPA, facilitates the intracellular processing of
lipids by hydrolyzing
cholesteryl esters and
triacylglycerols present in newly internalized
lipoproteins. Loss-of-function mutations in LIPA result in
cholesteryl ester storage disease (CESD) or
Wolman disease when mutations cause complete loss of LAL activity. Although the phenotype of a mouse CESD model has been extensively characterized, there has not been a focus on the brain at different stages of
disease progression. In the current studies, whole-brain mass and the concentrations of
cholesterol in both the esterified (EC) and unesterified (UC) fractions were measured in Lal-/- and matching Lal+/+ mice (FVB-N strain) at ages ranging from 14 up to 280 days after birth. Compared to Lal+/+ controls at 50, 68-76, 140-142, and 230-280 days of age, Lal-/- mice had brain weights that averaged approximately 6%, 7%, 18%, and 20% less, respectively. Brain EC levels were higher in the Lal-/- mice at every age, being elevated 27-fold at 230-280 days. Brain UC concentrations did not show a genotypic difference at any age. The elevated brain EC levels in the Lal-/- mice did not reflect EC in residual blood. An
mRNA expression analysis for an array of genes involved in the synthesis, catabolism, storage, and transport of
cholesterol in the brains of 141-day old mice did not detect any genotypic differences although the relative
mRNA levels for several markers of
inflammation were moderately elevated in the Lal-/- mice. The possible sites of EC accretion in the central nervous system are discussed.