Ethanol induces cholesterol efflux and up-regulates ATP-binding cassette cholesterol transporters in fetal astrocytes.
Cholesterol plays an important role during brain development, since it is involved in glial cell proliferation, neuronal survival and differentiation, and synaptogenesis. Astrocytes produce large amounts of brain cholesterol and produce and release lipoproteins containing apoE that can extract cholesterol from CNS cells for elimination. We hypothesized that some of the deleterious effects of ethanol in the developing brain may be due to the disruption of cholesterol homeostasis in astrocytes. This study investigates the effect of ethanol on cholesterol efflux mediated by ATP-binding cassette (ABC) cholesterol transporters. In fetal rat astrocytes in culture, ethanol caused a concentration-dependent increase in cholesterol efflux and increased the levels of ABCA1 starting at 25 mm. Similar effects of ethanol on cholesterol efflux and ABCA1 were also observed in fetal human astrocytes. In addition, ABCA1 levels were increased in the brains of 7-day-old pups treated for 3 days with 2, 4, or 6 g/kg ethanol. Ethanol also increased apoE release from fetal rat astrocytes, and conditioned medium prepared from ethanol-treated astrocytes extracted more cholesterol than conditioned medium from untreated cells. In addition, ethanol increased the levels of another cholesterol transporter, ABCG1. Ethanol did not affect cholesterol synthesis and reduced the levels of intracellular cholesterol in rat astrocytes. Retinoic acid, which induces teratogenic effects similarly to ethanol, also caused up-regulation of ABCA1 and ABCG1.
Guizzetti
Marina
M
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105, USA. marinag@u.washington.edu
Chen
Jing
J
Oram
John F
JF
Tsuji
Ryozo
R
Dao
Khoi
K
Möller
Thomas
T
Costa
Lucio G
LG
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002784:Cholesterol / Q000493:pharmacokinetics*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium; D015854:Up-Regulation / Q000187:drug effects
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D002492:Central Nervous System Depressants; D014316:Tritium; D000431:Ethanol; D002784:Cholesterol