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 develop therapeutic targets. We performed transcriptomic analysis on liver from rats with TPN administration, 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 prediction 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 administration. Hes6 may be a critical regulator for IFALD pathogenesis.