RNA-sequencing Identifies Novel Transcriptomic Signatures in Intestinal Failure-Associated Liver Disease.

Background: Total parenteral nutrition (TPN) dependence leads to development of intestinal failure -associated liver disease (IFALD). The spectrum of diseases ranges from cholestasis, steatosis, fibrosis, and cirrhosis that causes significant morbidity. Understanding the disease at molecular level helps us to de-velop therapeutic targets. We performed transcriptomic analysis on liver from rats with TPN adminis-tration, and we assessed the role of selected differentially expressed genes (DEGs), functional pathways, transcriptional factors, and their associations with pathological parameters of IFALD.Methods: Sprague-Dawley rats were subjected to TPN or standard chow with 0.9% saline for 7 days as controls. RNA-seq analysis was performed on liver samples. Correlations between transcriptional factor hairy and enhancer of split 6 (Hes6) and pathological parameters of IFALD were investigated.Results: We provided a comprehensive transcriptomic analysis to identify DEGs and functional pathways in liver from TPN-fed rats. We identified solute carrier family 7 member 11 (Slc7a11) as the most up -regulated mRNA, and ferroptosis-associated pathways were enriched in TPN group. Transcriptional factor (TF) analysis revealed that Hes6 interacted with Nr1d1, Tfdp2, Zbtb20, and Hmgb2l1. TF target gene pre-diction analysis suggested that Hes6 may regulate genes associated with bile acid secretion and fatty acid metabolism. Last, hepatic Hes6 expression was significantly decreased in TPN-fed rats, and was positively correlated with several taurine-conjugated bile acids and negatively correlated with hepatic triglyceride level. Conclusions: RNA-seq analysis revealed unique transcriptomic signatures in the liver following TPN ad-ministration. Hes6 may be a critical regulator for IFALD pathogenesis. (c) 2021 Elsevier Inc. All rights reserved.