Selective HIF stabilization alleviates hepatocellular steatosis and ballooning in a rodent model of 70% liver resection

Abstract

Background: Small-for-size syndrome looms over patients needing liver resection or living-donor transplantation. Hypoxia has been shown to be crucial for the successful outcome of liver resection in the very early postoperative phase. While poorly acceptable as such in real-world clinical practice, hypoxia responses can still be simulated by pharmacologically raising levels of its transducers, the hypoxia-inducible factors (HIF). We aimed to assess the potential role of a selective inhibitor of HIF degradation in 70% hepatectomy (70%Hx). Methods: In a pilot study, we tested the required dose of roxadustat to stabilize liver HIF1α. We then performed 70%Hx in 8-week-old male Lewis rats and administered 25 mg/kg of roxadustat (RXD25) at the end of the procedure. Regeneration was assessed: ki67 and EdU immunofluorescent labeling, and histological parameters. We also assessed liver function via a blood panel and functional gadoxetate-enhanced magnetic resonance imaging, up to 47 hours after the procedure. Metabolic results were analyzed by means of RNA sequencing. Results: Roxadustat effectively increased early HIF1α transactivity. Liver function did not appear to be improved nor liver regeneration to be accelerated by the experimental compound. However, treated livers showed a mitigation in hepatocellular steatosis and ballooning, known markers of cellular stress after liver resection. RNA sequencing confirmed that roxadustat unexpectedly increases lipid breakdown and cellular respiration. Conclusions: Selective HIF stabilization did not result in an enhanced liver function after standard liver resection, but it induced interesting metabolic changes that are worth studying for their possible role in extended liver resections and fatty liver diseases.

Hypoxia signaling in human health and diseases: implications and prospects for therapeutics

“…Roxadustat, for example, is primarily used to treat anemia in individuals with renal illness, but it has also been proven to affect hepatic lipolysis. 538,539 As a result, the danger that other non-diseased tissues may carry during administration should be thoroughly assessed. Even in the same tissue, HIF may play conflicting roles in various disease processes.…”

Roxadustat: do we know all the answers?

“…Roxadustat therapy reduces liver I/R injury through improving hepatic cell ballooning and steatosis while also promoting revascularization stability [ 89 , 90 ]. It has also been reported to protect against alcoholic hepatic disease by suppressing inflammation and ROS [ 91 , 92 ].…”