2型糖尿病（T2DM）人群中非酒精性脂肪性肝病（NAFLD）的患病率远高于普通人群，长期糖毒性对肝脏脂代谢的影响可能是其中的关键原因，但具体机制尚未阐明。表观遗传学中DNA甲基化研究得较为深入，它可体现长期代谢紊乱如糖毒性对基因水平的修饰和表达调控。我们前期用RRBS测序法检测T2DM患者与健康对照外周血DNA的甲基化情况，初筛出12个脂代谢相关基因甲基化差异区域，并在T2DM合并NAFLD小鼠模型的肝脏中验证，发现APLN和APLNR转录表达（mRNA水平）显著下调、且启动子区域均发生了高甲基化。由此我们提出：糖毒性可能通过增强肝脏APLN和APLNR基因启动子的甲基化、下调其转录表达，从而促进肝脏脂肪变性的发生。为验证该假说，我们将利用临床样本、多种体外细胞模型和T2DM合并NAFLD的动物模型，证明糖毒性对肝脏APLN和APLNR的DNA甲基化调控及其与肝脏脂肪变性发生之间的关系。

The prevalence of Nonalcoholic Fatty Liver Disease (NAFLD) in Type 2 Diabetic (T2DM) patients is much higher than that in general population. The effect of long-term glucotoxicity on lipid metabolism of the liver may be the key factor. However, the mechanism has not been clearly clarified. Epigenetics are studies about changes in gene expression that are not caused by changes in DNA sequences. Among them, DNA methylation is the most studied. DNA methylation can reflect the effect of long-term metabolic disorders such as glucotoxicity on the level of gene modification and expression regulation. We used RRBS method to detect the DNA methylation of peripheral blood in patients with T2DM and healthy controls, and screened out methylation differences area (DMR) of 12 lipid metabolism related genes between the two groups. We then verified that the mRNA level of APLN and APLNR is significantly lower and hypermethylation happens in the promoter regions in liver of a mouse model of T2DM with NAFLD. Therefore, we proposed that chronic glucotoxicity may promote the occurrence of hepatic steatosis by enhancing the methylation of APLN and APLNR gene promoters and down-regulating their transcriptional expression. Next, we will demonstrate the regulation of DNA methylation of APLN and APLNR caused by glucotoxicity and its causal relationship with NAFLD by using clinical samples, in vitro models and animal models of T2DM with NAFLD.