Abstract:
Alcoholic Steatohepatitis (ASH) is gradually advancing alcoholic liver disease (ALD) with hepatosteatosis, inflammation, and fibrosis. However, the molecular mechanism of ASH is incompletely understood. The orphan nuclear receptor Estrogen-Related Receptor Alpha (ERRa) and hypusination-mediated translation of EIF5A are the regulators of mitochondrial metabolism and energy homeostasis. Earlier studies showed their dysregulation was associated with hepatic inflammation and fibrosis during metabolic dysfunction-associated steatohepatitis (MASH). However, the role of ERRa-Hypusination in ASH is not known. This study investigated how ethanol exposure influences the ERRa signaling and the hypusination pathway in hepatocytes and the mouse liver. Using AML12 hepatocytes, ethanol exposure altered ERRa expression and significantly modulated the expression of genes regulating metabolic regulation and stress-response pathways. Ethanol treatment also altered the expression of key components of the hypusination machinery, suggesting disruption of translational regulatory processes. Pharmacological modulation of ERRa further influenced ethanol-induced gene and protein expression programs, indicating that ERRa regulates metabolic and stress-associated pathways under ethanol exposure. ERRa modulation also affected hypusination levels in ethanol-treated hepatocytes, suggesting functional crosstalk between ERRa signaling and the hypusination pathway. In vivo experiments using ethanol-fed mice showed that pharmacological inhibition of ERRa altered its hepatic expression. In addition, siRNA-mediated knockdown of ERRa and Deoxyhypusine Synthase (DHPS) reduced the Genistein-mediated increase in mitochondrial activity. These findings suggest that the ERRa-hypusination axis plays an important role in regulating mitochondrial activity in hepatocytes under ethanol stress. The results also indicate a potential interaction between ERRa signaling and the hypusination pathway in regulating mitochondrial function. Overall, this study highlights the role of ERRa signaling in metabolic dysfunction associated with alcoholic steatohepatitis and suggests its potential relevance as a therapeutic target in alcohol associated liver disease.
