Instituto de Investigaciones Médicas A Lanari, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; Departamento de Genética y Biología Molecular de Enfermedades Complejas, Instituto of Investigaciones Médicas (IDIM), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
Instituto de Investigaciones Médicas A Lanari, Facultad de Medicina, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina; Departamento de Hepatología Clínica y Molecular, Instituto of Investigaciones Médicas (IDIM), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
J Lipid Res. 2021;62:100073. doi: 10.1016/j.jlr.2021.100073. Epub 2021 May 5.
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver disease. Recent technological advances, combined with OMICs experiments and explorations involving different biological samples, have uncovered vital aspects of NAFLD biology. In this review, we summarize recent work by our group and others that expands what is known about the role of lipidome in NAFLD pathogenesis. We discuss how pathway and enrichment analyses were performed by integrating a list of query metabolites derived from text-mining existing NAFLD-lipidomics studies, resulting in the identification of nine Kyoto Encyclopedia of Genes and Genomes dysregulated pathways, including biosynthesis of unsaturated fatty acids, butanoate metabolism, synthesis and degradation of ketone bodies, sphingolipid, arachidonic acid and pyruvate metabolism, and numerous nonsteroidal antiinflammatory drug pathways predicted from The Small Molecule Pathway Database. We also summarize an integrated pathway-level analysis of genes and lipid-related metabolites associated with NAFLD, which shows overrepresentation of signal transduction, selenium micronutrient network, Class A/1Rhodopsin-like receptors and G protein-coupled receptor ligand binding, and G protein-coupled receptor downstream signaling. Generated gene-metabolite-disease interaction networks indicate that NAFLD and arterial hypertension are interlinked by molecular signatures. Finally, we discuss how mining pathways and associations among metabolites, lipids, genes, and proteins can be exploited to infer networks and potential pharmacological targets and how lipidomic studies may provide insight into the interrelationships among metabolite clusters that modify NAFLD biology, genetic susceptibility, diet, and the gut microbiome.
非酒精性脂肪性肝病（NAFLD）已成为最常见的慢性肝病。最近的技术进步，结合 OMICs 实验和不同生物样本的探索，揭示了 NAFLD 生物学的重要方面。在这篇综述中，我们总结了我们小组和其他小组的最新工作，这些工作扩展了脂质组在 NAFLD 发病机制中的作用的已知内容。我们讨论了如何通过整合从现有 NAFLD-脂质组学研究中提取的查询代谢物列表来进行途径和富集分析，从而确定了九个 Kyoto Encyclopedia of Genes 和 Genomes 失调途径，包括不饱和脂肪酸的生物合成、丁酸代谢、酮体的合成和降解、鞘脂、花生四烯酸和丙酮酸代谢以及来自 Small Molecule Pathway Database 的许多非甾体抗炎药途径。我们还总结了与 NAFLD 相关的基因和脂质相关代谢物的综合途径水平分析，结果表明信号转导、硒微量元素网络、A 类/1Rhodopsin 样受体和 G 蛋白偶联受体配体结合以及 G 蛋白偶联受体下游信号转导的代表性过高。生成的基因-代谢物-疾病相互作用网络表明，NAFLD 和动脉高血压通过分子特征相互关联。最后，我们讨论了如何挖掘代谢物、脂质、基因和蛋白质之间的途径和关联，以推断网络和潜在的药理靶点，以及脂质组学研究如何为改变 NAFLD 生物学、遗传易感性、饮食和肠道微生物组的代谢物簇之间的相互关系提供见解。
