Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig
Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig
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DOI：
10.1073/pnas.112336399
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发表时间：
2002-07-23
影响因子：
11.1
通讯作者：
James, SJ
中科院分区：
文献类型：
--
作者：
Halsted, CH;Villanueva, JA;James, SJ
酒精性肝病与肝脏甲硫氨酸代谢异常和叶酸缺乏有关。因为叶酸是蛋氨酸循环的组成部分，它的缺乏可以通过增强乙醇诱导的肝蛋氨酸代谢和DNA损伤的扰动来促进酒精性肝病。将24头小型猪分成两组，分别饲喂叶酸充足（IFS）、叶酸缺乏（FD）和含40%能量乙醇（FSE和FDE）的日粮，试验期14周，用方差分析确定各组间差异的显著性。血浆同型半胱氨酸水平在所有实验组从6周开始增加，并在FIDE中最大。乙醇喂养降低肝脏蛋氨酸合酶活性，S-腺苷蛋氨酸（SAM），谷胱甘肽，和升高血浆丙二醛（MDA）和丙氨酸转氨酶。叶酸缺乏会降低肝脏叶酸水平，并增加整体DNA低甲基化。乙醇喂养和叶酸缺乏共同作用，降低肝脏SAM/S-腺苷高半胱氨酸（SAH）比值，并增加肝脏SAH，DNA链断裂，尿8-氧代-2 '-脱氧鸟苷[oxo（8）dG]/mg肌酐，血浆同型半胱氨酸和天冬氨酸转氨酶超过8倍。肝SAM与谷胱甘肽呈正相关，谷胱甘肽与血浆MIDA和尿oxo（8）dG呈负相关。肝SAM/SAH与DNA链断裂呈负相关，DNA链断裂与尿oxo（8）dG相关。乙醇喂养动物的肝脏显示小叶中心CYP 2 E1和乙醛和MIDA的蛋白加合物增加。FDE组6头猪中有5头发生脂肪性肝炎，但其他组未发生。总之，叶酸缺乏增强肝甲硫氨酸代谢和DNA损伤的扰动，同时促进酒精性肝损伤。
Alcoholic liver disease is associated with abnormal hepatic methionine metabolism and folate deficiency. Because folate is integral to the methionine cycle, its deficiency could promote alcoholic liver disease by enhancing ethanol-induced perturbations of hepatic methionine metabolism and DNA damage. We grouped 24juvenile micropigs to receive folate-sufficient (IFS) or folate-depleted (FD) diets or the same diets containing 40% of energy as ethanol (FSE and FDE) for 14 wk, and the significance of differences among the groups was determined by ANOVA. Plasma homocysteine levels were increased in all experimental groups from 6 wk onward and were greatest in FIDE. Ethanol feeding reduced liver methionine synthase activity, S-adenosylmethionine (SAM), and glutathione, and elevated plasma malondialdehyde (MDA) and alanine transaminase. Folate deficiency decreased liver folate levels and increased global DNA hypomethylation. Ethanol feeding and folate deficiency acted together to decrease the liver SAM/S-adenosylhomocysteine (SAH) ratio and to increase liver SAH, DNA strand breaks, urinary 8-oxo-2'-deoxyguanosine [oxo(8)dG]/mg of creatinine, plasma homocysteine, and aspartate transaminase by more than 8-fold. Liver SAM correlated positively with glutathione, which correlated negatively with plasma MIDA and urinary oxo(8)dG. Liver SAM/SAH correlated negatively with DNA strand breaks, which correlated with urinary oxo(8)dG. Livers from ethanol-fed animals showed increased centrilobular CYP2E1 and protein adducts with acetaldehyde and MIDA. Steatohepatitis occurred in five of six pigs in FDE but not in the other groups. In summary, folate deficiency enhances perturbations in hepatic methionine metabolism and DNA damage while promoting alcoholic liver injury.