Identification of polyunsaturated fatty acids related key modules and genes in metabolic dysfunction-associated fatty liver disease using WGCNA analysis

Cheng Xiao; Siliang Chen; Chunru Yang; Jieying Liu; Miao Yu

doi:10.3389/fgene.2022.951224

Identification of polyunsaturated fatty acids related key modules and genes in metabolic dysfunction-associated fatty liver disease using WGCNA analysis

Front Genet. 2022 Nov 8:13:951224. doi: 10.3389/fgene.2022.951224. eCollection 2022.

Authors

Cheng Xiao¹, Siliang Chen^{2

3}, Chunru Yang¹, Jieying Liu^{1

4}, Miao Yu¹

Affiliations

¹ Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
² Department of Dermatology and Venereology, West China Hospital, Sichuan University, Chengdu, China.
³ Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Centre for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
⁴ Department of Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Abstract

Polyunsaturated fatty acids (PUFAs) play important roles in the aetiology and pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the underlying molecular mechanisms are not understood. We analysed a public GEO dataset, GSE89632, to identify differentially expressed genes (DEGs) in MAFLD. Weighted gene coexpression network analysis (WGCNA) was used to reveal the core gene regulation network and to explore the PUFA-related hub genes in MAFLD. We experimentally verified these genes by quantitative reverse transcription PCR in high-fat diet (HFD)-fed mice. A total of 286 common DEGs (89 upregulated; 197 downregulated), mostly related to inflammatory and immune responses, were identified. Six modules were constructed using WGCNA, and 2 modules showed significant correlations with PUFAs. After combining these 2 modules with DEGs, the top 10 hub genes were identified. We further established a MAFLD mouse model with liver steatosis, as proved by HE and Oil Red O staining. Of the hub genes, ADAM metallopeptidase with thrombospondin type 1 motif 1 (adamts1) (p = 0.005) and transforming growth factor β3 (tgfβ3) (p < 0.001) showed significantly lower mRNA expression in MAFLD in vivo. adamts1 and tgfβ3 bridged PUFAs and MAFLD, which might be potential causative genes and therapeutic targets of MAFLD.

Keywords: ADAMTS1 gene; TGFβ3 gene; WGCNA; differentially expressed genes; metabolic dysfunction-associated fatty liver disease; polyunsaturated fatty acids.