Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires, National Council of Scientific and Technological Research-CONICET, Autonomous City of Buenos Aires 1427, Argentina.
World J Gastroenterol. 2012 Nov 14;18(42):6018-26. doi: 10.3748/wjg.v18.i42.6018.
Genome-wide and candidate gene association studies have identified several variants that predispose individuals to developing nonalcoholic fatty liver disease (NAFLD). However, the gene that has been consistently involved in the genetic susceptibility of NAFLD in humans is patatin-like phospholipase domain containing 3 (PNPLA3, also known as adiponutrin). A nonsynonymous single nucleotide polymorphism in PNPLA3 (rs738409 C/G, a coding variant that encodes an amino acid substitution I148M) is significantly associated with fatty liver and histological disease severity, not only in adults but also in children. Nevertheless, how PNPLA3 influences the biology of fatty liver disease is still an open question. A recent article describes new aspects about PNPLA3 gene/protein function and suggests that the I148M variant promotes hepatic lipid synthesis due to a gain of function. We revise here the published data about the role of the I148M variant in lipogenesis/lipolysis, and suggest putative areas of future research. For instance we explored in silico whether the rs738409 C or G alleles have the ability to modify miRNA binding sites and miRNA gene regulation, and we found that prediction of PNPLA3 target miRNAs shows two miRNAs potentially interacting in the 3'UTR region (hsa-miR-769-3p and hsa-miR-516a-3p). In addition, interesting unanswered questions remain to be explored. For example, PNPLA3 lies between two CCCTC-binding factor-bound sites that could be tested for insulator activity, and an intronic histone 3 lysine 4 trimethylation peak predicts an enhancer element, corroborated by the DNase I hypersensitivity site peak. Finally, an interaction between PNPLA3 and glycerol-3-phosphate acyltransferase 2 is suggested by data miming.
全基因组和候选基因关联研究已经确定了几个变体，这些变体使个体易患非酒精性脂肪性肝病 (NAFLD)。然而，在人类中一直涉及 NAFLD 遗传易感性的基因是 patatin 样磷脂酶结构域包含 3 号（PNPLA3，也称为 adiponutrin）。PNPLA3 中的非同义单核苷酸多态性（rs738409 C/G，一种编码氨基酸取代 I148M 的编码变体）与脂肪肝和组织学疾病严重程度显著相关，不仅在成人中，而且在儿童中也如此。然而，PNPLA3 如何影响脂肪肝的生物学仍然是一个悬而未决的问题。最近的一篇文章描述了 PNPLA3 基因/蛋白功能的新方面，并表明 I148M 变体由于功能获得而促进肝内脂质合成。我们在这里修订了关于 I148M 变体在脂肪生成/脂肪分解中的作用的已发表数据，并提出了未来研究的可能领域。例如，我们在计算机上探索了 rs738409 的 C 或 G 等位基因是否有能力修饰 miRNA 结合位点和 miRNA 基因调控，我们发现 PNPLA3 靶 miRNA 的预测显示两个 miRNA 可能在 3'UTR 区域相互作用（hsa-miR-769-3p 和 hsa-miR-516a-3p）。此外，还有一些有趣的未解决的问题有待探索。例如，PNPLA3 位于两个 CCCTC 结合因子结合位点之间，这些位点可以测试其作为绝缘子的活性，并且内含子组蛋白 3 赖氨酸 4 三甲基化峰预测了一个增强子元件，这与 DNA 酶 I 超敏位点峰相吻合。最后，通过数据模拟提示 PNPLA3 与甘油-3-磷酸酰基转移酶 2 之间存在相互作用。
