Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action

Both genetic and lifestyle factors contribute to the risk of non-alcoholic steatohepatitis (NASH). Additionally, epigenetic modifications may also play a key role in the pathogenesis of NASH. We therefore investigated liver DNA methylation, as a marker for epigenetic alterations, in individuals with simple steatosis and NASH, and further tested if these alterations were associated with clinical phenotypes. Liver biopsies obtained from 95 obese individuals (age: 49.5 ± 7.7 years, BMI: 43 ± 5.7 kg/m2, type 2 diabetes [T2D]: 35) as a wedge biopsy during a Roux-en-Y gastric bypass operation were investigated. Thirty-four individuals had a normal liver phenotype, 35 had simple steatosis, and 26 had NASH. Genome-wide DNA methylation pattern was analyzed using the Infinium HumanMethylation450 BeadChip. mRNA expression was analyzed from 42 individuals using the HumanHT-12 Expression BeadChip. We identified 1,292 CpG sites representing 677 unique genes differentially methylated in liver of individuals with NASH (q LDHB (r = −0.45, P = 0.003). We demonstrated that NASH, more than simple steatosis, associates with differential DNA methylation in the human liver. These epigenetic alterations in NASH are linked with insulin metabolism.

遗传与生活方式因素均可提升非酒精性脂肪性肝炎（non-alcoholic steatohepatitis, NASH）的发病风险。此外，表观遗传修饰可能在NASH的发病机制中发挥关键作用。为此，本研究以肝脏DNA甲基化作为表观遗传改变的标志物，针对单纯性脂肪变性与NASH患者展开研究，并进一步验证此类表观遗传改变是否与临床表型存在关联。
本研究纳入95名肥胖受试者（年龄：49.5±7.7岁，体质量指数（Body Mass Index, BMI）：43±5.7 kg/m²，合并2型糖尿病（type 2 diabetes, T2D）者35例），所有受试者均在接受Roux-en-Y胃旁路手术时获取楔形肝脏活检组织用于后续分析。其中34名受试者肝脏表型正常，35名确诊为单纯性脂肪变性，26名确诊为NASH。
采用Infinium HumanMethylation450 BeadChip对全基因组DNA甲基化谱进行分析；采用HumanHT-12 Expression BeadChip对42名受试者的mRNA表达水平开展检测。
本研究在NASH患者的肝脏组织中鉴定出1292个差异甲基化CpG位点，涉及677个独特基因，其中与乳酸脱氢酶B（LDHB）的相关性系数为-0.45（P=0.003）。研究证实，相较于单纯性脂肪变性，NASH与人类肝脏的DNA甲基化差异关联更为显著。此类NASH相关的表观遗传改变与胰岛素代谢密切相关。