engleski

Altered expression of genes involved in cholesterol metabolism in the brain of ganglioside deficient mice

Major lipid constituents of mammalian cell membranes are cholesterol and glycosphingolipids, of which gangliosides are especially abundant in central nervous system. Cholesterol and gangliosides aggregate into lipid rafts involved in signal transduction, membrane trafficking and cell adhesion. In this study we examined the cholesterol metabolism in two knockout (KO) mouse models, St8sia1 and B4galnt1, whose phenotype includes impaired peripheral nerve regeneration and dysmyelination. St8sia1 mice lack the enzyme GD3 synthase while mice with a disrupted B4galnt1 gene lack GM2/GD2 synthase. The objective was to determine whether a change in ganglioside profile causes a perturbance of cholesterogenic genes expression in brain tissue of KO mice. Firstly we examined the brain ganglioside profile of both KO mouse models in comparison to wild type (wt) mice using high performance thin layer chromatography. We also determined the concentration of ganglioside-bound sialic acids of brain tissue samples of those mice. We then analyzed the expression of several cholesterogenic genes in several brain regions of KO and wt mice using quantitative real-time PCR. We found significantly higher gene expression in hippocampus of St8sia1 animals for lanosterol 14-alpha demethylase (Cyp51) involved in cholesterol synthesis and brain-specific cholesterol 24-hydroxylase (Cyp46) involved in cholesterol excretion from the brain. The change for both those genes in B4galnt1 mice whose phenotype is more severe was even more prominent. Cholesterol levels in serum of those mice were also measured, but did not differ significantly from the wt mice. Our results show that expression of genes involved in cholesterol synthesis and excretion is altered in the brain of KO mice. However, this perturbance does not result in changes of peripheral cholesterol concentration indicating higher cholesterol turnover in the brain of KO animals. We suggest that altered ganglioside profile, together with changed cholesterol metabolism can lead to alterations in intercellular interactions.

gangliosides; cholesterol; brain

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