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. 2022 Sep 17:2022:6161694.
doi: 10.1155/2022/6161694. eCollection 2022.

Noncoding RNAs Associated with PPARs in Etiology of MAFLD as a Novel Approach for Therapeutics Targets

Fatemeh Kazeminasab  1 , Maryam Baharlooie  2 , Kamran Ghaedi  2
Affiliations

Noncoding RNAs Associated with PPARs in Etiology of MAFLD as a Novel Approach for Therapeutics Targets

Fatemeh Kazeminasab et al. PPAR Res. .

Abstract

Background: 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. PPARγ 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this article.

Figures

Figure 1
Figure 1
Flowchart of the study.
Figure 2
Figure 2
KEGG pathway enrichment and protein-protein network of human MAFLD DEGs. (a) Top 5 enriched pathways with significant FDR score and (b) protein-protein network illustrating PPARs signaling genes as red and liver-expressed genes as blue nodes.
Figure 3
Figure 3
ClueGO results of interconnection between pathways in the network of human MAFLD DEGs. Hub pathways are shown as bigger nodes.
Figure 4
Figure 4
ClueGO results of interconnection between pathways in the network of mouse MAFLD DEGs. Hub pathways are shown as bigger nodes.
Figure 5
Figure 5
Strongly validated association of ncRNAs and PPARs. ncRNAs that are involved in MAFLD pathophysiology are depicted as bold titles with bordered nodes.
Figure 6
Figure 6
Interaction network construction and analysis of causal ncRNAs-fatty liver mRNAs. Hub genes and hub ncRNAs based on degree centrality parameter are showed as bigger nodes. MiRNAs, mRNAs, circular RNAs, and lncRNAs are depicted as yellow, green, blue, and turquoise nodes, respectively.
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