Gong Maokai, Castillo Leslie, Redman Robert S, Garige Mamatha, Hirsch Kenneth, Azuine Magnus, Amdur Richard L, Seth Devanshi, Haber Paul S, Lakshman M Raj
The Lipid Research Laboratory, Veterans Affairs Medical Center, The George Washington University, Washington, DC 20422, USA.
Metabolism. 2008 Dec;57(12):1663-8. doi: 10.1016/j.metabol.2008.07.021.
Hepatic steatosis and steatohepatitis are frequent results of long-term ethanol exposure. We have previously demonstrated that long-term ethanol down-regulates Galbetal, 4GlcNAc alpha2, 6-sialyltransferase (ST6Gal1), leading to defective glycosylation of a number of proteins including apolipoprotein (apo) E and apo J and the appearance of asialoconjugates in the blood of continuously alcohol-fed animals as well as in human alcoholics. In the current study, we have explored the possibility of whether ethanol-induced down-regulation of ST6Gal1 could contribute toward alcoholic steatosis in human alcoholics presumably because of impaired lipid and lipoprotein transport caused by this down-regulation. Real-time quantitative polymerase chain reaction analyses of liver samples from nondrinkers, moderate drinkers, and heavy drinkers as well as from subjects with and without alcoholic liver disease revealed direct evidence that the down-regulation of ST6Gal1 may be due to ethanol per se. The ST6Gal1 messenger RNA level was reduced by as much as 70% in moderate and heavy drinkers as well as in patients with alcoholic liver disease, but was not changed in subjects with liver disease due to causes other than alcohol exposure. Biochemical and histopathologic analysis demonstrated that the liver total cholesterol was increased by more than 30% (P < .05) and 75% (P < .01), respectively, in moderate and heavy drinkers compared with nondrinkers, with even more dramatic changes in triglyceride levels. Significantly, there was a strong inverse correlation between ST6Gal1 messenger RNA level and liver lipid deposit (F = 8.68, P < .001) by statistical analysis. Thus, it is suggested that alcohol-mediated down-regulation of hepatic ST6Gal1 gene leads to defective glycosylation of lipid-carrying apolipoproteins such as apo E and apo J, resulting in defective intracellular lipid and lipoprotein transport, which in turn may contribute to alcoholic steatosis.
肝脂肪变性和脂肪性肝炎是长期乙醇暴露的常见后果。我们之前已经证明，长期乙醇会下调β1,4-半乳糖基-2-N-乙酰氨基葡萄糖α2,6-唾液酸转移酶（ST6Gal1），导致包括载脂蛋白（apo）E和apo J在内的多种蛋白质糖基化缺陷，并且在持续饮酒的动物以及人类酗酒者的血液中出现去唾液酸糖缀合物。在当前研究中，我们探讨了乙醇诱导的ST6Gal1下调是否可能导致人类酗酒者出现酒精性脂肪变性，这可能是由于这种下调导致脂质和脂蛋白运输受损。对非饮酒者、适度饮酒者和重度饮酒者以及患有和未患有酒精性肝病的受试者的肝脏样本进行实时定量聚合酶链反应分析，揭示了直接证据表明STGal1下调可能是由于乙醇本身。在适度饮酒者、重度饮酒者以及酒精性肝病患者中，ST6Gal1信使核糖核酸水平降低了多达70%，但在因非酒精暴露原因导致肝病的受试者中未发生变化。生化和组织病理学分析表明，与非饮酒者相比，适度饮酒者和重度饮酒者的肝脏总胆固醇分别增加了30%以上（P <.05）和75%（P <.01），甘油三酯水平的变化甚至更为显著。通过统计分析，ST6Gal1信使核糖核酸水平与肝脏脂质沉积之间存在强烈的负相关（F = 8.68，P <.001）。因此，提示酒精介导的肝脏ST6Gal1基因下调导致携带脂质的载脂蛋白如apo E和apo J糖基化缺陷，导致细胞内脂质和脂蛋白运输缺陷，进而可能导致酒精性脂肪变性。
