Faculty of Pharmacy, University of Western Sydney, NSW, Australia.
J Pharm Pharm Sci. 2013;16(2):342-51. doi: 10.18433/j3788x.
Fatty liver disease, a hepatic manifestation of metabolic syndrome, is one of the major causes of chronic liver diseases. Epidemiological studies suggest that regular light-to-moderate ethanol consumption lowers the risk of developing metabolic disorders including dislipidemia, insulin resistance, type 2 diabetes and fatty liver disease. However, the mechanism(s) of the protective effect of light-to-moderate ethanol consumption on the liver remains unknown.
In the present study, we investigated the effects of light (6%, 0.94 g/kg/day) and moderate (12%, 1.88 g/kg/day) ethanol feeding in rats for 3 weeks on the circulating and hepatic biochemical profiles and on the hepatic protein expression and phosphorylation status of adenosine monophosphate-activated protein kinase-α (AMPK-α) and other down-stream targets of this enzyme including sterol regulatory element-binding protein-1 (SREBP-1), SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase).
Despite no significant difference in food-intake among the groups, light ethanol treatment significantly increased the body weight compared to control rats. Serum glucose, insulin, total cholesterol, triglycerides, phospholipids and hepatic cholesterol and triglycerides were not significantly different among the groups. However, serum free fatty acids were significantly reduced with light ethanol treatment. Both light and moderate ethanol treatment significantly increased the hepatic levels of phosphorylated AMPK-α protein and this was associated with significant reduction of SREBP-1 protein expression, suggesting an enhanced fatty acid oxidation. In addition, light ethanol treatment significantly decreased the SCAP protein expression in the liver. However, liver HMG-CoA protein expression was not significantly different with ethanol consumption.
Chronic light-to-moderate ethanol consumption increased AMPK activation which was associated with decreased expression of SREBP-1 and SCAP in the liver. Thus, our studies provide mechanistic evidence for the earlier epidemiological studies that indicate light-to-moderate ethanol intake lowers the risk of development of fatty liver disease and other metabolic disorders. Our studies demonstrate that the protective effects of light-to-moderate ethanol arise at least in part by increased phosphorylation of AMPK-α and decreased SREBP-1 expression in the liver. Further studies are warranted to determine the effects of light-to-moderate ethanol on intracellular up-stream and down-stream targets of AMPK and also on the implications of light-to-moderate ethanol in protecting non-alcoholic fatty liver disease.
脂肪肝疾病是代谢综合征的一种肝脏表现，是慢性肝脏疾病的主要原因之一。流行病学研究表明，有规律的少量至中等量饮酒可降低发生代谢紊乱的风险，包括血脂异常、胰岛素抵抗、2 型糖尿病和脂肪肝疾病。然而，少量至中等量饮酒对肝脏的保护作用的机制尚不清楚。
在本研究中，我们研究了大鼠 3 周内轻（6%，0.94 g/kg/天）和中（12%，1.88 g/kg/天）乙醇喂养对循环和肝生化谱以及肝腺苷单磷酸激活蛋白激酶-α（AMPK-α）的蛋白表达和磷酸化状态和该酶的其他下游靶标，包括固醇调节元件结合蛋白-1（SREBP-1）、SREBP 切割激活蛋白（SCAP）和 3-羟-3-甲基戊二酰辅酶 A 还原酶（HMG-CoA 还原酶）的影响。
尽管各组之间的食物摄入量没有明显差异，但轻乙醇处理组与对照组大鼠相比，体重显著增加。血清葡萄糖、胰岛素、总胆固醇、甘油三酯、磷脂和肝胆固醇及甘油三酯在各组之间无显著差异。然而，血清游离脂肪酸随着轻乙醇处理而显著降低。轻和中乙醇处理均显著增加肝磷酸化 AMPK-α蛋白水平，这与 SREBP-1 蛋白表达的显著降低有关，提示脂肪酸氧化增强。此外，轻乙醇处理组肝 SCAP 蛋白表达明显降低。然而，乙醇摄入对肝 HMG-CoA 蛋白表达无明显影响。
慢性少量至中等量乙醇摄入增加了 AMPK 的激活，这与肝 SREBP-1 和 SCAP 表达的降低有关。因此，我们的研究为早期流行病学研究提供了机制证据，表明少量至中等量乙醇摄入可降低脂肪肝疾病和其他代谢紊乱的发病风险。我们的研究表明，少量至中等量乙醇的保护作用至少部分是由于肝磷酸化 AMPK-α的增加和 SREBP-1 表达的降低。还需要进一步的研究来确定少量至中等量乙醇对 AMPK 的细胞内上游和下游靶标以及少量至中等量乙醇在保护非酒精性脂肪肝疾病中的意义的影响。
