title: Impact of heme oxygenase-1 on cholesterol synthesis, cholesterol efflux and oxysterol formation in cultured astroglia.
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 (Fe(2+)), 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 ( approximately 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. beta-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.
authors.affiliation: Centre for Neurotranslational Research, Lady Davis Institute for Medical Research, SMBD Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Jacob R
authors.initials: JR
authors.lastname: Hascalovici
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.forename: Jacob
authors.initials: J
authors.lastname: Vaya
authors.forename: Soliman
authors.initials: S
authors.lastname: Khatib
authors.forename: Bianca
authors.initials: B
authors.lastname: Fuhrman
authors.forename: Michael
authors.initials: M
authors.lastname: Aviram
authors.forename: Hyman M
authors.initials: HM
authors.lastname: Schipper
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001663:Bilirubin / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002248:Carbon Monoxide / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000502:physiology*; D000071518:Liver X Receptors; D008665:Metalloporphyrins / Q000494:pharmacology; D009566:Nitrates / Q000494:pharmacology; D009571:Nitrilotriacetic Acid / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology; D057093:Orphan Nuclear Receptors; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005290:Ferric Compounds; D000071518:Liver X Receptors; D008665:Metalloporphyrins; D009566:Nitrates; D009942:Organometallic Compounds; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C476530:tricarbonylchloro(glycinato)ruthenium(II); C055421:tin mesoporphyrin; D002248:Carbon Monoxide; D002784:Cholesterol; D051547:Heme Oxygenase-1; D009571:Nitrilotriacetic Acid; C025302:ferric nitrate; D001663:Bilirubin