Department of Human Nutrition, University of Illinois at Chicago, Illinois 60612, USA.
Alcohol Clin Exp Res. 2010 Mar 1;34(3):471-8. doi: 10.1111/j.1530-0277.2009.01111.x. Epub 2009 Dec 18.
Chronic alcohol consumption causes alcoholic liver disease, which is associated, or initiated, with dysregulated lipid metabolism. Very recent evidence suggested that dysregulated cholesterol metabolism plays an important role in the pathogenesis of alcoholic fatty liver diseases, however, the effects of chronic alcohol exposure on cholesterol homeostasis have not been well studied and underlying mechanisms behind are still elusive.
Male Sprague-Dawley rats weighing 250 +/- 5.5 g (mean +/- SEM) divided into 2 groups (8 rats per group) and pair-fed with liquid diets containing (in percent of energy intake) 18% protein, 35% fat, 12% carbohydrate, and 35% either ethanol (ethanol diet) or an isocaloric maltose-dextrin mixture (control diet), according to Lieber and De Carli, for 4 weeks.
Long-term excessive alcohol feeding to rats caused fatty liver and liver injury, which was associated with disrupted cholesterol homeostasis, characterized by increased hepatic cholesterol levels and hypercholesterolemia. Hepatic cholesterol increases were concomitant with constantly activated sterol regulatory element-binding protein-2 (SREBP-2) in the liver and increased expression of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, a rate-limiting enzyme for cholesterol de novo synthesis, indicating enhanced cholesterol biosynthesis. Alcohol-induced hypercholesterolemia was accompanied by decreased LDL receptor (LDLr) levels in the liver. Further investigations revealed that chronic alcohol exposure increased hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) contents to down-regulate LDLr via a post-translational mechanism. Moreover, alcohol feeding suppressed extracellular signal-regulated kinase (ERK) activation in the liver. In vitro studies showed that inhibition of ERK activation was associated with decreased LDLr expression in HepG2 cells.
Our study provides the first evidence that both increased PCSK9 expression and suppressed ERK activation in the liver contributes to alcohol-induced hypercholesterolemia in rats.
慢性酒精摄入会导致酒精性肝病，而后者与脂质代谢失调有关，或由其引发。最近的证据表明，胆固醇代谢失调在酒精性脂肪肝疾病的发病机制中起着重要作用，然而，慢性酒精暴露对胆固醇稳态的影响尚未得到很好的研究，其潜在机制仍不清楚。
雄性 Sprague-Dawley 大鼠体重 250 ± 5.5 g（平均值 ± SEM），分为 2 组（每组 8 只大鼠），并根据 Lieber 和 De Carli 的方法，用含有（占能量摄入的百分比）18%蛋白质、35%脂肪、12%碳水化合物和 35%乙醇（乙醇饮食）或等热量麦芽糊精混合物（对照饮食）的液体饮食进行喂养 4 周。
长期过量饮酒会导致大鼠脂肪肝和肝损伤，这与胆固醇稳态失调有关，其特征为肝胆固醇水平升高和高胆固醇血症。肝胆固醇的增加与肝中固醇调节元件结合蛋白-2（SREBP-2）的持续激活以及 3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶的表达增加有关，HMG-CoA 还原酶是胆固醇从头合成的限速酶，表明胆固醇生物合成增强。酒精引起的高胆固醇血症伴随着肝内 LDL 受体（LDLr）水平的降低。进一步的研究表明，慢性酒精暴露会增加肝前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型（PCSK9）的含量，通过翻译后机制下调 LDLr。此外，酒精喂养抑制了肝外信号调节激酶（ERK）的激活。体外研究表明，ERK 激活的抑制与 HepG2 细胞中 LDLr 表达的降低有关。
我们的研究首次提供了证据表明，肝脏中 PCSK9 表达的增加和 ERK 激活的抑制都有助于大鼠酒精性高胆固醇血症的发生。
