Key result
NAFLD and NASH pathogenesis involves altered metabolism, inflammation, and cholesterol synthesis pathways, with SREBF1, TNF, and IL1B identified as key upstream regulators.
Why the study?
To examine genetic expression in NAFLD and NASH tissue samples to identify common pathways contributing to disease pathogenesis under the multiple hit model.
Meta-Analysis (n=459)
Transcriptomic analysis identifies distinct molecular pathways and upstream regulators, such as SREBF1 in NAFLD and cholesterol synthesis in NASH, highlighting potential therapeutic targets like AKT and PI3K inhibitors.
Highlights SREBF1 and cholesterol pathways in NAFLD/NASH; extends transcriptomic data but remains hypothesis-generating for targeted therapies.
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and globally. The currently understood model of pathogenesis consists of a 'multiple hit' hypothesis in which environmental and genetic factors contribute to hepatic inflammation and injury. AIM: To examine the genetic expression of NAFLD and non-alcoholic steatohepatitis (NASH) tissue samples to identify common pathways that contribute to NAFLD and NASH pathogenesis. METHODS: We employed the Search Tag Analyze Resource for Gene Expression Omnibus platform to search the The National Center for Biotechnology Information Gene Expression Omnibus to elucidate NAFLD and NASH pathology. For NAFLD, we conducted meta-analysis of data from 58 NAFLD liver biopsies and 60 healthy liver biopsies; for NASH, we analyzed 187 NASH liver biopsies and 154 healthy liver biopsies. RESULTS: Our results from the NAFLD analysis reinforce the role of altered metabolism, inflammation, and cell survival in pathogenesis and support recently described contributors to disease activity, such as altered androgen and long non-coding RNA activity. The top upstream regulator was found to be sterol regulatory element binding transcription factor 1 (SREBF1), a transcription factor involved in lipid homeostasis. Downstream of SREBF1, we observed upregulation in CXCL10, HMGCR, HMGCS1, fatty acid binding protein 5, paternally expressed imprinted gene 10, and downregulation of sex hormone-binding globulin and insulin-like growth factor 1. These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver. Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis. Top canonical pathways, disease networks, and disease functions were related to cholesterol synthesis, lipid metabolism, adipogenesis, and metabolic disease. Top upstream regulators included pro-inflammatory cytokines tumor necrosis factor and IL1B, PDGF BB, and beta-estradiol. Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism, extracellular matrix deposition, and tumor suppression. Lastly, we found riciribine (an AKT inhibitor) and ZSTK-474 (a PI3K inhibitor) as potential drugs that targeted the differential gene expression in our dataset. CONCLUSION: In this study we describe several molecular processes that may correlate with NAFLD disease and progression. We also identified ricirbine and ZSTK-474 as potential therapy.
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Aljabban et al. (2022) conducted a meta-analysis in Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) (n=459). NAFLD and NASH vs. Healthy liver biopsies was evaluated on Differential gene expression and pathway analysis. NAFLD and NASH pathogenesis involves altered metabolism, inflammation, and cholesterol synthesis pathways, with SREBF1, TNF, and IL1B identified as key upstream regulators.
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