Scientific Article
The Role of Hypoxia-Inducible Factor 1 Alpha in Acute-on-Chronic Liver Failure
Acute-on-chronic liver failure (ACLF) is associated with increased mortality. Specific therapy options are limited. Hypoxia-inducible factor 1 alpha (HIF-1α) has been linked to the pathogenesis of chronic liver disease (CLD), but the role of HIF-1α in ACLF is poorly understood. In the current study, different etiologies of CLD and precipitating events triggering ACLF were used in four rodent models. HIF-1α expression and the intracellular pathway of HIF-1α induction were investigated using real-time quantitative PCR. The results were verified by Western blotting and immunohistochemistry for extrahepatic HIF-1α expression using transcriptome analysis. Exploratory immunohistochemical staining was performed to assess HIF-1α in human liver tissue. Intrahepatic HIF-1α expression was significantly increased in all animals with ACLF, regardless of the underlying etiology of CLD or the precipitating event. The induction of HIF-1α was accompanied by the increased mRNA expression of NFkB1 and STAT3 and resulted in a marked elevation of mRNA levels of its downstream genes. Extrahepatic HIF-1α expression was not elevated. In human liver tissue samples, HIF-1α expression was elevated in CLD and ACLF. Increased intrahepatic HIF-1α expression seems to play an important role in the pathogenesis of ACLF, and future studies are pending to investigate the role of therapeutic HIF inhibitors in ACLF.
Mücke, M.M., El Bali, N., Schwarzkopf, K.M., Uschner, F.E., Kraus, N., Eberle, L., Mücke, V.T., Bein, J., Beyer, S., Wild, P.J., Schierwagen, R., Klein, S., Zeuzem, S., Welsch, C., Trebicka, J., Brieger, A. The Role of Hypoxia-Inducible Factor 1 Alpha in Acute-on-Chronic Liver Failure. Int J Mol Sci. 2024 Jan 26;25(3):1542. doi: 10.3390/ijms25031542. PMID: 38338821; PMCID: PMC10855542.
