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J. Biol. Chem., Vol. 282, Issue 26, 18740-18749, June 29, 2007

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Ethanol Induces Cholesterol Efflux and Up-regulates ATP-binding Cassette Cholesterol Transporters in Fetal Astrocytes^*

Marina Guizzetti¹, Jing Chen, John F. Oram, Ryozo Tsuji^¶, Khoi Dao, Thomas Möller^||, and Lucio G. Costa^**

From the Department of Environmental and Occupational Health Sciences, Department of Medicine, and ^||Department of Neurology, University of Washington, Seattle, Washington 98105, the ^¶Environmental Health Laboratory, Sumitomo Chemical Co. Ltd., Osaka 554-8558, Japan, and the ^**Department of Human Anatomy, Pharmacology and Forensic Medicine, University of Parma, 43100 Parma, Italy

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.

Received for publication, March 20, 2007 , and in revised form, May 1, 2007.

^* This research was supported in part by National Institutes of Health Grants AA015443, AA08154, P30ES07033, and HD00836 and by a grant from Alcohol and Drug Abuse Institute, University of Washington. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Environmental and Occupational Health Sciences, University of Washington, 4225 Roosevelt Way N.E. #100, Seattle, WA 98105. Tel.: 206-543-8644; Fax: 206-685-4696; E-mail: marinag{at}u.washington.edu.

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