早期单纯性脂肪肝基因组学改变  

Genomic changes in early stage of fatty liver

作　　者：慕开达[1] 朱云霞[2] 王士洪[2] 王琛[2] 贾伟平[2] 

机构地区：[1]苏州大学医学部,江苏苏州215123 [2]上海交通大学附属第六人民医院内分泌科,上海交通大学糖尿病研究所,上海市糖尿病重点实验室

出　　处：《上海医学》2013年第5期429-432,I0001,共5页Shanghai Medical Journal

摘　　要：目的检测轻微脂肪肝患者全基因组表达,探索早期单纯性脂肪肝相关基因的改变。方法肝外科收集肝脏良性疾病的手术标本,各选取4例脂肪变性的肝细胞占肝组织切片<5%的样本(对照组)和脂肪变性的肝细胞占肝组织切片15%～25%的样本(脂肪肝组)。对两组进行基因芯片检测,对差异基因进行生物学分析及应用实时荧光定量聚合酶链反应验证。结果共得出128个差异基因。各样本差异基因表达结果均可区分对照组与脂肪肝组;脂肪肝组上调基因占63%,下调基因占37%;对照组上调基因占37%,下调基因占63%。102个基因参与分子功能;103个基因参与细胞成分;97个基因参与生物学过程,其中53个基因参与代谢过程。合成通路中,脂肪肝组甘油磷酸代谢通路上调,其关键酶1酰基甘油3磷酸O酰基转移酶2(AGPAT2)、甘油激酶基因表达为对照组的1.6(P=0.006)及2.1倍(P=0.037);脂肪酸从头合成通路下调,其关键酶乙酰COA酶羧化酶(ACACA)、脂肪酸合成酶(FASN)及脂肪酸延长酶(ELOVL6)的基因表达为对照组的60%(P=0.003)、40%(P=0.011)和40%(P=0.032);脂肪肝组脂肪酸摄取通路中膜蛋白CD36表达上调,为对照组的1.4倍(P=0.038);两组间参与脂肪酸β氧化的通路关键酶肉毒碱棕榈酰基转移酶及极低密度脂蛋白分泌的关键酶微粒体三酰甘油转移酶表达的差异均无统计学意义(P值均>0.05);两组间调控三酰甘油合成的转录因子,固醇调节元件结合蛋白1、核因子、过氧化物酶体增生物激活受体α/λ的差异也无统计学意义(P值均>0.05),但脂肪肝组新发现的调控因子——成纤维细胞生长因子21(FGF21)显著上调,为对照组的2.0倍(P=0.04)。结论单纯性脂肪肝早期,脂肪摄取及三酰甘油合成基因上调,但脂肪酸从头合成基因下调,表明脂肪摄取增多及三酰甘油合成增加可能是促进早期单纯性脂肪肝进展的重要因素。Objective To detect the whole genome expression in patients with mild fatty liver and to explore the changes of related genes in the early stage of nonalcoholic fatty liver disease （NAFLD）. Methods Hepatic tissues were obtained from patients with benign focal hepatic lesions treated by liver surgery. Affymatrix GeneChip Human Genome U133 Plus 2.0 Array was used to investigate the gene expression in 4 samples with early-stage hepatic steatosis （ 15 %- 25% of hepatocytes with fat, fatty liver group） and 4 samples without fatty liver （〈5% of hepatocytes with fat, control group）. Real-time polymerase chain reaction （PCR） was used for the confirmation of differential genes. Results A total of 128 differential genes were identified from the samples. Among them, 63% were up-regulated and 37% were down-regulated in the fatty liver group; 37% were up- regulated and 63% were down-regulated in the control group. There were 102 genes participating in molecular function and 103 genes being cell components, 97 genes related to biologic process, and 53 genes involved in metabolic process. Pathway analysis showed that genes involved in triglyceride synthesis （1-acylglycerol-3- phosphate O-acyltransferase 2[AGPAT2], glycerol kinase） and fatty acid transport （CD36） were upregulated, while genes involved in de novo fatty acicl synthesis （chinken acetyl-coenzyme a carboxylase alpha [ACACA], fatty acid synthase [FASNT, elongation of very long chain fatty acids protein 6, [ELOVL6]） were down-regulated in subjects with fatty liver. The gene expression of AGPAT2 and glycerol kinase and protein level of CD36 in fattyliver group were 1.6 times, 2.1 times and 1.4 times higher than the control group （ P = 0. 006, 0. 037 and 0. 038, respectively）. The gene expression of ACACA, FASN and ELOVL6 in fatty liver group was 60% （ P = 0. 003）, 40 % （ P = 0.011 ） and 40 % （ P = 0. 032） of the control group respectively. There were no significant differences in the expression of carnitine palmityl transfer

关 键 词：非酒精性脂肪肝 基因芯片 脂代谢 早期脂肪变性 

分 类 号：R575.5[医药卫生—消化系统]