Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Second University of Naples, Naples, Italy.
PLoS One. 2013 Aug 19;8(8):e71391. doi: 10.1371/journal.pone.0071391. eCollection 2013.
The importance of genetics and epigenetic changes in the pathogenesis of non alcoholic fatty liver disease (NAFLD) has been increasingly recognized. Adiponectin has a central role in regulating glucose and lipid metabolism and controlling inflammation in insulin-sensitive tissues and low adiponectin levels have been linked to NAFLD. APPL1 and APPL2 are adaptor proteins that interact with the intracellular region of adiponectin receptors and mediate adiponectin signaling and its effects on metabolism. The aim of our study was the evaluation of a potential association between variants at APPL1 and APPL2 loci and NAFLD occurrence. The impact on liver damage and hepatic steatosis severity has been also evaluated. To this aim allele frequency and genotype distribution of APPL1- rs3806622 and -rs4640525 and APPL2-rs 11112412 variants were evaluated in 223 subjects with clinical diagnosis of NAFLD and compared with 231 healthy subjects. The impact of APPL1 and APPL2 SNPs on liver damage and hepatic steatosis severity has been also evaluated. The minor-allele combination APPL1-C/APPL2-A was associated with an increased risk of NAFLD (OR = 2.50 95% CI 1.45-4.32; p<0.001) even after adjustment for age, sex, body mass index, insulin resistance (HOMA-IR), triglycerides and adiponectin levels. This allele combination carrier had higher plasma alanine aminotransferase levels (Diff = 15.08 [7.60-22.57] p = 0.001) and an increased frequency of severe steatosis compared to the reference allele combination (OR = 3.88; 95% CI 1.582-9.531; p<0.001). In conclusion, C-APPL1/A-APPL2 allele combination is associated with NAFLD occurrence, with a more severe hepatic steatosis grade and with a reduced adiponectin cytoprotective effect on liver.
非酒精性脂肪性肝病（NAFLD）发病机制中遗传和表观遗传变化的重要性日益受到重视。脂联素在调节葡萄糖和脂质代谢以及控制胰岛素敏感组织中的炎症方面起着核心作用，而脂联素水平低与 NAFLD 有关。APPL1 和 APPL2 是与脂联素受体细胞内区相互作用并介导脂联素信号及其对代谢影响的衔接蛋白。我们的研究目的是评估 APPL1 和 APPL2 基因座的变异与 NAFLD 发生之间的潜在关联。还评估了对肝损伤和肝脂肪变性严重程度的影响。为此，评估了 APPL1-rs3806622 和 -rs4640525 以及 APPL2-rs11112412 变体在 223 例临床诊断为 NAFLD 的患者中的等位基因频率和基因型分布，并与 231 例健康对照进行比较。还评估了 APPL1 和 APPL2 SNPs 对肝损伤和肝脂肪变性严重程度的影响。APPL1-C/APPL2-A 等位基因组合与 NAFLD 风险增加相关（OR=2.50，95%CI 1.45-4.32；p<0.001），即使在调整年龄、性别、体重指数、胰岛素抵抗（HOMA-IR）、甘油三酯和脂联素水平后也是如此。与参考等位基因组合相比，这种等位基因组合的携带者具有更高的血浆丙氨酸氨基转移酶水平（差异=15.08[7.60-22.57]，p=0.001）和更频繁的严重脂肪变性（OR=3.88；95%CI 1.582-9.531；p<0.001）。总之，C-APPL1/A-APPL2 等位基因组合与 NAFLD 的发生相关，与更严重的肝脂肪变性程度相关，并且对肝脏的脂联素细胞保护作用降低。
