Chronic Voluntary Ethanol Consumption Induces Favorable Ceramide Profiles in Selectively Bred Alcohol-Preferring (P) Rats
Chronic Voluntary Ethanol Consumption Induces Favorable Ceramide Profiles in Selectively Bred Alcohol-Preferring (P) Rats
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DOI：
10.1371/journal.pone.0139012
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发表时间：
2015-09-25
期刊：
影响因子：
3.7
通讯作者：
Brasser, Susan M.
中科院分区：
文献类型：
--
作者：
Godfrey, Jessica;Jeanguenin, Lisa;Brasser, Susan M.
大量饮酒会对神经系统产生有害影响，会导致胎儿和成年人出现广泛的神经元丢失。在充分暴露的情况下，乙醇诱导的细胞损失的一个被提出的机制是介导细胞凋亡的生物活性脂的浓度增加，包括膜鞘磷脂代谢物神经酰胺和鞘氨醇。虽然这些自然产生的脂质是正常神经元发育的重要调节因子，但各种细胞外损伤导致的水平升高与几种神经炎性和神经退行性疾病中神经元和少突胶质细胞的病理性凋亡有关。先前的工作已经表明，对发育中的小鼠急性给予乙醇会增加多个脑区神经酰胺的水平，这些脑区被认为是胎儿酒精诱导的神经元丢失的媒介。神经酰胺水平升高也与成年动物和人类的乙醇介导的神经退行性变有关。在这里，我们确定了长期自愿饮酒对成年饮酒(P)大鼠脑和周围组织脂质谱的影响，以进一步检验脂质成分的变化作为酒精诱导细胞损伤的潜在贡献者。将大鼠暴露在20%酒精间歇饮用模式下13周(总共45次酒精饮酒)，或只给予水(对照)。在最后一次会议之后，收集组织用于随后的脂类含量和酶基因表达的层析分析。与预期相反，酒精暴露的大鼠显示出与未暴露的对照组相比，前脑和心脏中神经酰胺的浓度显著降低，肝脏胆固醇略有但显著下降。QRT-PCR分析显示神经酰胺合成过程中神经鞘脂脂Delta(4)-去饱和酶(Degs2)的表达降低。这些发现表明，由于长期自愿暴露，偏爱酒精的P鼠达到的酒精摄入量水平可能对该基因系中的血脂谱有有利的影响，而不是有害的影响，这与支持适度酒精摄入有益的心脏保护和神经保护作用的数据一致。
Heavy alcohol consumption has detrimental neurologic effects, inducing widespread neuronal loss in both fetuses and adults. One proposed mechanism of ethanol-induced cell loss with sufficient exposure is an elevation in concentrations of bioactive lipids that mediate apoptosis, including the membrane sphingolipid metabolites ceramide and sphingosine. While these naturally-occurring lipids serve as important modulators of normal neuronal development, elevated levels resulting from various extracellular insults have been implicated in pathological apoptosis of neurons and oligodendrocytes in several neuroinflammatory and neurodegenerative disorders. Prior work has shown that acute administration of ethanol to developing mice increases levels of ceramide in multiple brain regions, hypothesized to be a mediator of fetal alcohol-induced neuronal loss. Elevated ceramide levels have also been implicated in ethanol-mediated neurodegeneration in adult animals and humans. Here, we determined the effect of chronic voluntary ethanol consumption on lipid profiles in brain and peripheral tissues from adult alcohol-preferring (P) rats to further examine alterations in lipid composition as a potential contributor to ethanol-induced cellular damage. P rats were exposed for 13 weeks to a 20% ethanol intermittent-access drinking paradigm (45 ethanol sessions total) or were given access only to water (control). Following the final session, tissues were collected for subsequent chromatographic analysis of lipid content and enzymatic gene expression. Contrary to expectations, ethanol-exposed rats displayed substantial reductions in concentrations of ceramides in forebrain and heart relative to non-exposed controls, and modest but significant decreases in liver cholesterol. qRT-PCR analysis showed a reduction in the expression of sphingolipid delta(4)-desaturase (Degs2), an enzyme involved in de novo ceramide synthesis. These findings indicate that ethanol intake levels achieved by alcohol-preferring P rats as a result of chronic voluntary exposure may have favorable vs. detrimental effects on lipid profiles in this genetic line, consistent with data supporting beneficial cardioprotective and neuroprotective effects of moderate ethanol consumption.