Perturbation of Wnt/β-catenin signaling and sexual dimorphism in non-alcoholic fatty liver disease.

RNA-seq; RT2-profiler PCR arrays; Wnt/β-catenin; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; sexual dimorphism; Hepatology; Infectious Diseases

Abstract :

[en] [en] AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH) is higher in postmenopausal women than men. The aim of this study was to determine the molecular mechanisms underlying this sexual dimorphism in NAFLD. METHODS: A total of 24 frozen liver samples of both sexes (normal and NAFLD/NASH) were used in this study. Total RNAseq was first used to identify differentially expressed genes (DEGs) between samples. Enrichment analysis of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome were used to analyze biological pathways. RT2 profiler polymerase chain reaction (PCR) arrays were used to identify genes associated with the biological pathways. Immunoblotting was used to validate protein expression of certain genes. RESULTS: We identified 4362 genes that are differentially expressed between NAFLD/NASH and normal samples; of those 745 genes were characterized as sex specific in NAFLD/NASH. Multiple pathway analysis platforms showed that Wnt-signaling is a candidate shared for a common biological pathway-associated with NAFLD/NASH. Using Wnt pathway focused PCR array we identified many genes involved in canonical pathway (Wnt/β-catenin activation) such as CTNNB1, c-Myc and CCND2 are overexpressed in female cases, whereas these genes are either not detected or downregulated in male cases. Immunoblot analysis validated the expression of CTNNB1 in female cases but not in male protein samples. CONCLUSIONS: Our study suggests, for the first time, that the activation of canonical Wnt signaling could be one of the main pathways associated with sexual dimorphism in NAFLD and NASH.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Yeh, Matthew M ; Department of Laboratory Medicine and Pathology, University of Washington, School of Medicine, Seattle, Washington, USA

Shi, Xiuhui ; Université de Liège - ULiège > Département de pharmacie ; Department of Medicine and Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

Yang, Jingxuan ; Department of Medicine and Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

Li, Min ; Department of Medicine and Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

Fung, Kar-Ming ; Department of Pathology and Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

Daoud, Sayed S ; Department of Pharmaceutical Sciences, Washington State University Health Sciences, Spokane, Washington, USA

Language :

English

Title :

Perturbation of Wnt/β-catenin signaling and sexual dimorphism in non-alcoholic fatty liver disease.

Publication date :

May 2022

Journal title :

Hepatology research : the official journal of the Japan Society of Hepatology

ISSN :

1386-6346

eISSN :

1872-034X

Publisher :

John Wiley and Sons Inc, Netherlands

Volume :

Issue :

Pages :

433 - 448

Peer reviewed :

Peer reviewed

Additional URL :

https://onlinelibrary.wiley.com/doi/pdf/10.1111/hepr.13754

Funding text :

The human liver specimens were obtained through the Liver Tissue Cell Distribution System (Minneapolis, MN), which is funded by the National Institute of Health Contract No. N01-DK-7-0004/HHSN267200700004C. This work was supported by CPPS-WSU (17A-2957-9838) to SD.The human liver specimens were obtained through the Liver Tissue Cell Distribution System (Minneapolis, MN), which is funded by the National Institute of Health Contract No. N01‐DK‐7‐0004/HHSN267200700004C. This work was supported by CPPS‐WSU (17A‐2957‐9838) to SD.

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