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

Abstract

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.

Glia and Neurodevelopment: Focus on Fetal Alcohol Spectrum Disorders

“…We have shown that ethanol increases ABCA1 and ABCG1 levels, induces cholesterol efflux, and reduces cholesterol levels in primary rat astrocytes in culture (137). Interestingly, isotretinoin, which causes developmental effects similar to ethanol, induces ABCA1 and ABCG1 expression, increases cholesterol efflux, and decreases cholesterol content in astrocytes similarly to ethanol (137, 138), suggesting a common mechanism of teratogenesis (133).…”

“…Interestingly, isotretinoin, which causes developmental effects similar to ethanol, induces ABCA1 and ABCG1 expression, increases cholesterol efflux, and decreases cholesterol content in astrocytes similarly to ethanol (137, 138), suggesting a common mechanism of teratogenesis (133). These observations were also confirmed in in vivo FASD models.…”

“…These observations were also confirmed in in vivo FASD models. Indeed, neonatal alcohol exposure increases cortical levels of ABCA1 (137); furthermore, prenatal alcohol exposure upregulates ABCA1 and ABCG1 and reduces the levels of cholesterol in the neocortex of GD 21 female fetuses (139). Figure 3 shows a proposed model of the interactions of astrocytes and neurons in cholesterol homeostasis and the effects of ethanol.…”

Ethanol-induced changes in poly (ADP ribose) polymerase and neuronal developmental gene expression

“…To reduce ethanol evaporation, cultures were placed in sealed chambers with a reservoir tray containing water supplemented with ethanol at the same concentration used in the culture medium (50 mM) and gassed with a 5% CO2-95% air gas mixture. Under these conditions, no significant ethanol loss was observed at the end of the incubations (Guizzetti et al, 2007). Rosiglitazone (Sigma-Aldrich, St. Louis, MO), ABT-888 (Veliparib) (Selleck Chemicals, Houston, TX), 3AB (Trevigen, Gaithersburg, MD), or Rucaparib (Selleck Chemicals, Houston, TX) were added to cultures in the presence and in the absence of ethanol.…”

Role of plasma phospholipid transfer protein in lipid and lipoprotein metabolism

“…One of those was related to the role of PLTP and ABCA1 in the brain [133]. PLTP is expressed in the brain, and it is secreted by neurons and glial cells [22, 23].…”