Cholesterol homeostasis has been proposed to be implicated in the development of addiction. However, the effects of ethanol on cholesterol homeostasis within the brain are not well understood. One of the most important regulators of cholesterol homeostasis is HMG-CoA reductase (HMG-CoAR), the rate-limiting enzyme of cholesterol biosynthesis. We examined the phosphorylation of HMG-CoAR and the other key regulator of lipid synthesis, acetyl-CoA carboxylase (ACC), following acute or chronic treatment with ethanol (0.5, 1, or 2 g/kg) in the rat prefrontal cortex. The phosphorylation of AMP-activated protein kinase (AMPK), which regulates the HMG-CoAR activity, and its well-known upstream regulators, was also studied. The phosphorylation of HMG-CoAR and ACC were transiently increased by ethanol treatment only in animals previously treated chronically with ethanol. Acute administration to naïve animals did not induce the phosphorylation, regardless of dosage. Similarly, the phosphorylation of AMPK and the upstream regulators, LKB1 and CaMK4, were transiently increased only in chronically ethanol-treated animals. In naïve animals, a high dose (2 g/kg) of ethanol decreased phosphorylation. The phosphorylation of TAK1, another upstream kinase of AMPK, was increased only from 30 min to 24 h after the chronic treatment with ethanol. Together, these results indicate that repeated exposure is required for the activating effect of ethanol on HMG-CoAR and ACC. This effect seems to be mediated by the AMPK system, and may contribute to the long-lasting neuroadaptation involved in the development of alcohol dependence.

中文翻译：

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反复暴露于乙醇会通过大鼠前额叶皮层中的AMPK途径影响胆固醇和脂质体内稳态中的关键酶。

胆固醇稳态被认为与成瘾的发展有关。但是，乙醇对脑内胆固醇稳态的影响尚不清楚。胆固醇稳态的最重要调节剂之一是HMG-CoA还原酶（HMG-CoAR），它是胆固醇生物合成的限速酶。我们在大鼠前额叶皮层中用乙醇（0.5、1或2 g / kg）急性或慢性治疗后，检查了HMG-CoAR的磷酸化和脂质合成的另一个关键调节剂乙酰-CoA羧化酶（ACC）。还研究了调节HMG-CoAR活性的AMP活化蛋白激酶（AMPK）的磷酸化及其众所周知的上游调节剂。HMG-CoAR和ACC的磷酸化仅在先前用乙醇长期治疗的动物中通过乙醇处理而瞬时增加。不论剂量如何，对幼稚动物的急性给药均不会引起磷酸化。同样，AMPK和上游调节剂LKB1和CaMK4的磷酸化仅在经过长期乙醇治疗的动物中短暂增加。在幼稚的动物中，高剂量（2 g / kg）的乙醇会降低磷酸化作用。用乙醇进行慢性处理后，TAK1（AMPK的另一种上游激酶）的磷酸化仅从30分钟增加到24小时。总之，这些结果表明，乙醇对HMG-CoAR和ACC的活化作用需要反复暴露。这种效果似乎是由AMPK系统介导的，