Molecular markers of brain cholesterol homeostasis are unchanged despite a smaller brain mass in a mouse model of cholesteryl ester storage disease

Abstract

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 À/À 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 À/À mice had brain weights that averaged approximately 6%, 7%, 18%, and 20% less, respectively. Brain EC levels were higher in the Lal À/À 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 À/À 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 À/À mice. The possible sites of EC accretion in the central nervous system are discussed. K E Y W O R D S brain mass, cholesterol-esterifying enzymes, esterified cholesterol sequestration, lysosomal acid lipase, residual blood volume, unesterified cholesterol

Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency

“…LAL-D is a multi-system disorder, affecting liver, spleen, intestines, lungs, brain, and blood, as well as bone. 31 , 32 We sought to get LIPA expression throughout the body to get maximal trans effects from overexpression, as extracellular LAL can be taken up by other cells though mannose 6-phosphate receptor-mediated endocytosis, 33 much as occurs with enzyme replacement therapy. Though we saw high levels of AAV vgs in many organs, including the liver, we often did not detect corresponding increases in gene expression.…”

Rescue of lysosomal acid lipase deficiency in mice by rAAV8 liver gene transfer

“…As a consequence, LAL-D patients suffer from hepatosplenomegaly, elevated circulating alanine (ALT) and aspartate (AST) transaminases due to liver damage and hyperlipidemia with elevated low-density (LDL) and reduced high-density lipoprotein (HDL). Unlike other lysosomal storage disorders, LAL-D does not obviously affect the central nervous system ( 1 , 2 ). The severity of the disorder depends on the residual amount of functional LAL enzyme.…”