School of Medicine, Institute of Medical Research ALanari, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET)-University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires, Argentina.
Hepatology. 2020 Jul;72(1):330-346. doi: 10.1002/hep.31229.
Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning worldwide epidemic whose etiology reflects multiple interactions between environmental and genetic factors. Here, we review the major pathways and dominant genetic modifiers known to be relevant players in human NAFLD and which may determine key components of the heritability of distinctive disease traits including steatosis and fibrosis. In addition, we have employed general assumptions which are based on known genetic factors in NAFLD to build a systems biology prediction model that includes functional enrichment. This prediction model highlights additional complementary pathways that represent plausible intersecting signaling networks that we define here as an NAFLD-Reactome. We review the evidence connecting variants in each of the major known genetic modifiers (variants in patatin-like phospholipase domain containing 3, transmembrane 6 superfamily member 2, membrane-bound O-acyltransferase domain containing 7, glucokinase regulator, and hydroxysteroid 17-beta dehydrogenase 13) to NAFLD and expand the associated underlying mechanisms using functional enrichment predictions, based on both preclinical and cell-based experimental findings. These major candidate gene variants function in distinct pathways, including substrate delivery for de novo lipogenesis; mitochondrial energy use; lipid droplet assembly, lipolytic catabolism, and fatty acid compartmentalization; and very low-density lipoprotein assembly and secretion. The NAFLD-Reactome model expands these pathways and allows for hypothesis testing, as well as serving as a discovery platform for druggable targets across multiple pathways that promote NAFLD development and influence several progressive outcomes. In conclusion, we summarize the strengths and weaknesses of studies implicating selected variants in the pathophysiology of NAFLD and highlight opportunities for future clinical research and pharmacologic intervention, as well as the implications for clinical practice.
非酒精性脂肪性肝病 (NAFLD) 是一种在全球范围内迅速流行的疾病，其病因反映了环境和遗传因素之间的多种相互作用。在这里，我们回顾了已知与人类 NAFLD 相关的主要途径和主要遗传修饰因子，这些因子可能决定了疾病特征（包括脂肪变性和纤维化）的遗传率的关键组成部分。此外，我们还运用了基于 NAFLD 中已知遗传因素的一般假设，构建了一个包含功能富集的系统生物学预测模型。该预测模型突出了其他可能的互补途径，这些途径代表了我们在此定义的作为 NAFLD-Reactome 的可能交汇信号网络。我们回顾了连接主要已知遗传修饰因子（载脂蛋白样磷脂酶结构域 3、跨膜 6 超家族成员 2、膜结合酰基转移酶结构域 7、葡萄糖激酶调节剂和羟甾体 17-β 脱氢酶 13 中的变体）中每个变体与 NAFLD 的连接的证据，并使用基于临床前和基于细胞的实验发现的功能富集预测，扩展了相关的潜在机制。这些主要候选基因变体在不同的途径中发挥作用，包括从头合成脂肪所需的底物传递；线粒体能量利用；脂滴组装、脂解代谢和脂肪酸区室化；以及极低密度脂蛋白的组装和分泌。NAFLD-Reactome 模型扩展了这些途径，并允许进行假设检验，同时作为促进 NAFLD 发展和影响多种进展性结果的多个途径的药物靶点发现平台。总之，我们总结了涉及选定变体在 NAFLD 病理生理学中的作用的研究的优缺点，并强调了未来临床研究和药物干预的机会，以及对临床实践的影响。
