Kazeminasab Fatemeh, Baharlooie Maryam, Ghaedi Kamran
Department of Physical Education and Sport Sciences, Faculty of Humanities, University of Kashan, Ravand Street, Kashan 87317-35153, Iran.
Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar Jerib Avenue, Azadi Sq., Isfahan 81746-73441, Iran.
PPAR Res. 2022 Sep 17;2022:6161694. doi: 10.1155/2022/6161694. eCollection 2022.
Metabolic associated fatty liver disease (MAFLD) is a complex disease that results from the accumulation of fat in the liver. MAFLD is directly associated with obesity, insulin resistance, diabetes, and metabolic syndrome. PPAR ligands, including pioglitazone, are also used in the management of this disease. Noncoding RNAs play a critical role in various diseases such as diabetes, obesity, and liver diseases including MAFLD. However, there is no adequate knowledge about the translation of using these ncRNAs to the clinics, particularly in MAFLD conditions. The aim of this study was to identify ncRNAs in the etiology of MAFLD as a novel approach to the therapeutic targets.
We collected human and mouse MAFLD gene expression datasets available in GEO. We performed pathway enrichment analysis of total mRNAs based on KEGG repository data to screen the most potential pathways in the liver of MAFLD human subjects and mice model, and analyzed pathway interconnections via ClueGO. Finally, we screened disease causality of the MAFLD ncRNAs, which were associated with PPARs, and then discussed the role of revealed ncRNAs in PPAR signaling and MAFLD.
We found 127 ncRNAs in MAFLD which 25 out of them were strongly validated before for regulation of PPARs. With a polypharmacology approach, we screened 51 ncRNAs which were causal to a subset of diseases related to MAFLD.
This study revealed a subset of ncRNAs that could help in more clear and guided designation of preclinical and clinical studies to verify the therapeutic application of the revealed ncRNAs by manipulating the PPARs molecular mechanism in MAFLD.
代谢相关脂肪性肝病（MAFLD）是一种因肝脏脂肪堆积而导致的复杂疾病。MAFLD与肥胖、胰岛素抵抗、糖尿病和代谢综合征直接相关。包括吡格列酮在内的过氧化物酶体增殖物激活受体（PPAR）配体也用于该疾病的治疗。非编码RNA在糖尿病、肥胖症以及包括MAFLD在内的肝脏疾病等多种疾病中发挥着关键作用。然而，对于将这些非编码RNA应用于临床，尤其是在MAFLD情况下，我们还缺乏足够的了解。本研究的目的是鉴定MAFLD病因中的非编码RNA，作为一种确定治疗靶点的新方法。
我们收集了基因表达综合数据库（GEO）中可用的人类和小鼠MAFLD基因表达数据集。我们基于京都基因与基因组百科全书（KEGG）数据库数据对所有mRNA进行通路富集分析，以筛选MAFLD人类受试者和小鼠模型肝脏中最具潜力的通路，并通过ClueGO分析通路间的相互联系。最后，我们筛选了与PPAR相关的MAFLD非编码RNA的疾病因果关系，然后讨论了所揭示的非编码RNA在PPAR信号传导和MAFLD中的作用。
我们在MAFLD中发现了127种非编码RNA，其中25种之前已被充分验证可调节PPAR。通过多药理学方法，我们筛选出了51种与MAFLD相关的部分疾病有因果关系的非编码RNA。
本研究揭示了一部分非编码RNA，它们有助于更清晰、有针对性地设计临床前和临床研究，通过操纵MAFLD中的PPAR分子机制来验证所揭示的非编码RNA的治疗应用。
