Cholesterol and oxygenated cholesterol concentrations are markedly elevated in peripheral tissue but not in brain from mice with the Niemann-Pick type C phenotype

摘要: Niemann–Pick disease type C (NP-C) is a rare genetic disorder characterized by progressive neurodegeneration, frequent developmental delay and early death. Tissues of affected individuals accumulate large quantities free cholesterol in lysosomes. Because cytotoxic oxygenated derivatives are known to form readily when concentrations elevated, we searched for these compounds liver, kidney, spleen brain from mice with the NP-C phenotype. In order abundance, identified 7α- 7β-hydroxycholesterol, 5α,6α-epoxycholestan-3β-ol, 4β-hydroxycholesterol, cholest-4-en-3β,7α-diol cholest-4-en-3β,6β-diol most tissue samples. Cholesterol were increased 3-fold kidney 7- 8-fold liver compared controls (all p<0.001) but unchanged brain. Although oxysterol levels markedly elevated non-brain tissue, proportionally so that oxysterols expressed as percentage total sterols same all animals (0.34±0.19% averaged over organs vs 0.40±0.42% control mice). contrast peripheral could not detect any increase either absolute or relative brains (49±61 53±43 μg/g wet weight 0.45±0.52 0.47±0.37%, respectively). Thus, normal it unlikely an accumulation account neuropathology seen disease.