Potz Brittany A, Lawandy Isabella J, Clements Richard T, Sellke Frank W
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island.
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island.
J Surg Res. 2016 Jun 1;203(1):154-62. doi: 10.1016/j.jss.2016.03.009. Epub 2016 Mar 24.
Autophagy serves as a cellular protective mechanism against alcohol-induced tissue injury but excessive autophagy can also be detrimental leading to apoptosis. Our laboratory has previously shown that moderate alcohol consumption alters expression of proteins in the insulin signaling pathway and worsens glucose metabolism in the liver in a swine model of metabolic syndrome. We examined the effect of alcohol consumption on apoptosis and autophagy signaling in the liver in our clinically relevant animal model of chronic hypercholesterolemia.
Twenty-six Yorkshire swine were fed a high-fat diet for 4 wks and were then split into three groups: hypercholesterolemic diet alone (HCC, n = 9), hypercholesterolemic diet with vodka (hypercholesterolemic vodka [HCV], n = 9), and hypercholesterolemic diet with wine (hypercholesterolemic wine [HCW], n = 8) for 7 wks. Animals underwent euthanasia, and liver tissue samples were harvested for analysis. Liver tissue was analyzed via Western blot analysis. Protein density data were normalized to GAPDH and is reported as fold-change values ± standard error of the mean compared to the high-cholesterol diet control group. A Kruskal-Wallis test with a Dunn's multiple comparison test was used to compare the means among groups.
The HCV group showed significant increases in several proapoptotic proteins (including caspase 3, caspase 8, caspase 9, and cleaved caspase 9) compared with the HCC group. There was a decrease in the proapoptotic protein (BAD) and an increase in anti-apoptotic signal (B-cell lymphoma-2) in the HCW group compared with HCC control. There were increases in pro-survival proteins (AKT, p-AKT, mTOR, p-mTOR) in the HCW and the HCV group compared with control (HCC). There were decreases in autophagy protein LCB-3 in the HCW and HCV compared with the control.
We found that moderate alcohol consumption altered protein expression related to apoptosis and autophagy signaling in pig liver in the setting of hypercholesterolemia. Interestingly, vodka may induce proapoptotic pathways in liver tissue, whereas wine may induce anti-apoptotic signaling. These results provide a mechanism by which vodka may contribute to alcoholic liver disease and supports the notion that wine, containing resveratrol, may prevent cellular apoptosis in liver tissue in the setting of hypercholesterolemia.
自噬作为一种细胞保护机制，可抵御酒精诱导的组织损伤，但过度自噬也可能有害，导致细胞凋亡。我们实验室先前已表明，在代谢综合征的猪模型中，适度饮酒会改变胰岛素信号通路中蛋白质的表达，并使肝脏中的葡萄糖代谢恶化。我们在慢性高胆固醇血症的临床相关动物模型中，研究了饮酒对肝脏中细胞凋亡和自噬信号传导的影响。
26只约克夏猪接受高脂饮食4周，然后分为三组：单纯高胆固醇饮食组（HCC，n = 9）、高胆固醇饮食加伏特加组（高胆固醇伏特加[HCV]组，n = 9）和高胆固醇饮食加葡萄酒组（高胆固醇葡萄酒[HCW]组，n = 8），持续7周。对动物实施安乐死，并采集肝脏组织样本进行分析。通过蛋白质印迹分析对肝脏组织进行分析。将蛋白质密度数据以甘油醛-3-磷酸脱氢酶（GAPDH）进行标准化，并报告为与高胆固醇饮食对照组相比的倍数变化值±平均标准误差。采用Kruskal-Wallis检验和Dunn多重比较检验来比较各组均值。
与HCC组相比，HCV组中几种促凋亡蛋白（包括半胱天冬酶3、半胱天冬酶8、半胱天冬酶9和裂解的半胱天冬酶9）显著增加。与HCC对照组相比，HCW组中促凋亡蛋白（BAD）减少，抗凋亡信号（B细胞淋巴瘤-2）增加。与对照组（HCC）相比，HCW组和HCV组中促存活蛋白（AKT、p-AKT、mTOR、p-mTOR）增加。与对照组相比，HCW组和HCV组中自噬蛋白LCB-3减少。
我们发现，在高胆固醇血症背景下，适度饮酒会改变猪肝中与细胞凋亡和自噬信号传导相关的蛋白质表达。有趣的是，伏特加可能诱导肝脏组织中的促凋亡途径，而葡萄酒可能诱导抗凋亡信号。这些结果提供了一种机制，通过该机制伏特加可能导致酒精性肝病，并支持了含有白藜芦醇的葡萄酒可能预防高胆固醇血症背景下肝脏组织细胞凋亡的观点。
