Modifications of cholesterol metabolism in brain following uranium contamination

Titre du congrès :4ème Congrès de Lipidomique Ville du congrès :Toulouse Date du congrès :09/10/2007

Cholesterol is essential to human health due to its diverse roles, ranging from membrane structure and fluidity to synthesis of numerous molecules such as steroid hormones, vitamin D and bile acids. Cholesterol is also involved in myelin synthesis, thus in central nervous system functioning. Moreover, it is well established that some disruptions of cholesterol metabolism in the brain can lead to pathological outcomes, such as Alzheimer's disease or Niemann-Pick C disease. Recent work showed that brain could be targeted by uranium, a natural radionuclide. Uranium's occurrence in the environment results from both natural and human origins. Its enrichment in nuclear power plants produces two compounds: enriched uranium (EU) and depleted uranium (DU). The dispersion of uranium in the environment sets human populations at risk of being contaminated through ingestion, inhalation or skin penetration. After entering the body, uranium builds up in several organs, including brain where it can induce behaviour disorders such as changes in sleep/wake cycles , anxiety and memory troubles after chronic contamination. Considering the importance of cholesterol in the brain in the light of these data, we studied the effect of uranium contamination on cerebral cholesterol metabolism. Therefore, rats were exposed during 9 months to DU or EU through drinking water at a concentration of 40 mg/l (twice the highest environmental level, equivalent to 1 mg/rat/day). After DU contamination, the HDL-cholesterol level in plasma decreased (25%) whereas plasma level of 27-hydroxycholesterol increased (200%). The mRNA levels of several proteins involved in cerebral cholesterol metabolism were modified. Gene expression of CYP46A1, responsible for the synthesis of 24S-hydroxycholesterol, was increased by 39%. HMGCoA Synthase (HMGS) mRNA levels rose from 91%. Gene expression of three proteins involved in cholesterol transport was also modified: SR-B1 (+34%), ABC A1 (+34%) and Apo E (+75%). Finally, mRNA levels of nuclear receptors PPAR and PPAR were increased (46% and 36% respectively). Conversely, gene expression of RXR was reduced by 29%. DU contamination enhance at the same time pathways that increase the cholesterol pool in the cell (uptake via SR-B1 and Apo E, synthesis via HMGS) and pathways that lead cholesterol out of the cell (detoxification via CYP46A1 and efflux via ABC A1). This would lead to an overall balanced cholesterol pool in the brain: whatever pathways are primarily altered by DU, the compensatory pathways are also activated. Besides, it is noteworthy that the modification of HDL-cholesterol and 27-hydroxycholesterol plasma levels might foreshadow a disruption of cholesterol metabolism at body level. Further investigation is needed to assess if DU has an effect on animals susceptible to a neurological pathology (Alzheimer's disease).