The pathogenesis of ethanol versus methionine and choline deficient diet-induced liver injury
The pathogenesis of ethanol versus methionine and choline deficient diet-induced liver injury
复制标题
DOI：
10.1016/j.bcp.2007.09.030
复制
发表时间：
2008-02-15
影响因子：
5.8
通讯作者：
Wan, Yu-Jui Yvonne
中科院分区：
文献类型：
--
作者：
Gyamfi, Maxwell Afari;Damjanov, Ivan;Wan, Yu-Jui Yvonne
探讨酒精性脂肪性肝炎（ASH）和非酒精性脂肪性肝炎（NASH）发病机制的异同。小鼠（6只/组）接受4种Lieber-Decarli液体饲料中的一种，持续6周：（1）配对饲喂对照饲料;（2）含乙醇（乙醇）的对照饲料;（3）配对饲喂蛋氨酸/胆碱缺乏（MCD）饲料;和（4）MCD+乙醇（组合）。检查肝毒性、组织学和基因表达变化。MCD和乙醇均诱导大泡性脂肪变性。然而，组合饮食产生大量脂肪变性，伴有轻微坏死和炎症。MCD和组合饮食，但不是乙醇，诱导血清ALT水平分别为1.6倍和10倍。MCD饲料（而非乙醇）也诱导血清碱性磷酸酶水平，表明胆管损伤。乙醇增加肝脏脂肪酸结合蛋白（L-FABP）mRNA和蛋白水平。与此相反，组合饮食降低L-FABP mRNA和蛋白水平，并增加肝脏游离脂肪酸和脂质过氧化物水平。乙醇（而非MCD）可降低肝S-腺苷甲硫氨酸（SAM）和GSH水平。所有给药组的肝脏TNF α蛋白水平均升高，然而，IL-6（一种促进肝再生的保肝细胞因子）在乙醇喂养小鼠中升高（2倍），但在联合饲料处理小鼠中降低。此外，组合饮食降低了磷酸化STAT 3和Bcl-2水平。虽然MCD饮食可能导致胆管损伤和胆汁淤积，但乙醇优先干扰SAM-GSH氧化应激途径。由组合饮食诱导的肝损伤加重可能由L-FABP降低、游离脂肪酸增加、氧化应激和IL-6蛋白水平降低来解释。组合饮食是脂肪性肝炎的有效模型。爱思唯尔公司出版
The differences and similarities of the pathogenesis of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) were examined. Mice (six/group) received one of four Lieber-Decarli liquid diets for 6 weeks: (1) paired-fed control diet; (2) control diet with ethanol (ethanol); (3) paired-fed methionine/choline deficient (MCD) diet; and (4) MCD plus ethanol (combination). Hepatotoxicity, histology, and gene expression changes were examined. Both MCD and ethanol induced macrovesicular steatosis. However, the combination diet produced massive steatosis with minor necrosis and inflammation. MCD and combination diets, but not ethanol, induced serum ALT levels by 1.6- and 10-fold, respectively. MCD diet, but not ethanol, also induced serum alkaline phosphatase levels suggesting bile duct injury. Ethanol increased liver fatty acid binding protein (L-FABP) mRNA and protein levels. in contrast, the combination diet decreased L-FABP mRNA and protein levels and increased hepatic free fatty acid and lipid peroxide levels. Ethanol, but not MCD, reduced hepatic S-adenosylmethionine (SAM) and GSH levels. Hepatic TNF alpha protein levels were increased in all treatment groups, however, IL-6, a hepatoprotective cytokine which promotes liver regeneration was increased in ethanol-fed mice (2-fold), but decreased in the combination diet-treated mice. In addition, the combination diet reduced phosphorylated STAT3 and Bcl-2 levels. While MCD diet might cause bile duct injury and cholestasis, ethanol preferentially interferes with the SAM-GSH oxidative stress pathway. The exacerbated liver injury induced by the combination diet might be explained by reduced L-FABP, increased free fatty acids, oxidative stress, and decreased IL-6 protein levels. The combination diet is an efficient model of steatohepatitis. Published by Elsevier Inc.