Meta-analysis illustrates roles of cholesterol synthesis, dysregulated apoptosis, and other processes in nash pathogenesis.
Aljabban J, Khorfan K, Aljabban I, Aljabban H, Foflonker K, Panahiazar M, and Hadley D. Meta-analysis illustrates roles of cholesterol synthesis, dysregulated apoptosis, and other processes in nash pathogenesis. Hepatology 2018; 68:747A.
Background: Non-alcoholic steatosis (NASH) is a form of non-alcoholic fatty liver disease (NAFLD) characterized by inflammation. NASH can progress to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. While the pathogenesis of NASH remains unclear, excess lipid storage, insulin resistance, and increased formation of reactive oxidation species are thought to be involved. Methods: The NCBI Gene Expression Omnibus (GEO) is an open database of more than 2 million samples of functional genomics experiments. The Search Tag Analyze Resource for GEO (STARGEO) platform allows for meta-analysis of genomic signatures of disease and tissue. We employed the STARGEO platform to search the GEO and performed meta-analysis on 187 NASH liver samples, using 154 healthy liver samples as a control. We then analyzed the signature in Ingenuity Pathway Analysis (IPA) to help define the genomic signature of NASH and identify disease pathways. Results: We identified several cholesterol biosynthesis pathways as top canonical pathways, including cholesterol synthesis via 24, 25-dihydrolanosterol, desmosterol, and the superpathway. IGF1 signaling was also a top canonical pathway and is a proven indicator of NASH severity. TNF, PDGF BB (negatively correlated with fibrosis), and beta-estradiol were top regulators. We found upregulation of genes involved in fat synthesis, transport, and accumulation including crystallin (CRYAA) and gamma-butyrobetaine hydroxylase 1 (BBOX1). Notably, we saw upregulation of the novel myokine fibronectin type 3 (FNDC5), which correlated with NAFLD severity and extracellular matrix deposition. Our genetic analysis also highlighted dysregulated apoptosis through the downregulation of pro-apoptotic regulators such as the matricellular protein CYR61, FOS protein (modulates JUN signaling), and RASD1 from the RAS family. The downregulation of our top regulator PDFG BB also suggests dysregulated apoptosis and increased risk for fibrosis. Lastly, we found decreased insulin sensitivity through downregulation of nicotinamide phosphoribosyltransferase (NAMPT). Conclusion: Our analysis suggests that NASH pathogenesis is complex and includes several pathophysiological processes including excess cholesterol biosynthesis and fat accumulation, extracellular matrix deposition, insulin resistance, and dysregulated apoptosis. We identified several molecules that drive these processes and demonstrated their regulation by PDGF BB (figure 1). These molecules can serve as biomarkers and PDGF BB is a promising therapeutic target.