Impact of heme oxygenase-1 on cholesterol synthesis, cholesterol efflux and oxysterol formation in cultured astroglia |
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Authors: | Jacob R Hascalovici† Wei Song Jacob Vaya‡ Soliman Khatib‡ Bianca Fuhrman§ Michael Aviram§ Hyman M Schipper† |
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Institution: | Centre for Neurotranslational Research, Lady Davis Institute for Medical Research, SMBD Jewish General Hospital, Montreal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada; Laboratory of Natural Medicinal Compounds, Migal-Galilee Technological Center, Kiryat-Shmona, Israel; The Lipid Research Laboratory, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, Haifa, Israel |
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Abstract: | Up-regulation of heme oxygenase-1 (HO-1) and altered cholesterol (CH) metabolism are characteristic of Alzheimer-diseased neural tissues. The liver X receptor (LXR) is a molecular sensor of CH homeostasis. In the current study, we determined the effects of HO-1 over-expression and its byproducts iron (Fe2+), carbon monoxide (CO) and bilirubin on CH biosynthesis, CH efflux and oxysterol formation in cultured astroglia. HO-1/LXR interactions were also investigated in the context of CH efflux. hHO-1 over-expression for 3 days (∼2–3-fold increase) resulted in a 30% increase in CH biosynthesis and a two-fold rise in CH efflux. Both effects were abrogated by the competitive HO inhibitor, tin mesoporphyrin. CO, released from administered CORM-3, significantly enhanced CH biosynthesis; a combination of CO and iron stimulated CH efflux. Free iron increased oxysterol formation three-fold. Co-treatment with LXR antagonists implicated LXR activation in the modulation of CH homeostasis by heme degradation products. In Alzheimer's disease and other neuropathological states, glial HO-1 induction may transduce ambient noxious stimuli (e.g. β-amyloid) into altered patterns of glial CH homeostasis. As the latter may impact synaptic plasticity and neuronal repair, modulation of glial HO-1 expression (by pharmacological or other means) may confer neuroprotection in patients with degenerative brain disorders. |
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Keywords: | Alzheimer's disease cholesterol heme oxygenase-1 LXR oxidative stress oxysterols |
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