Aquaporin five deficiency suppresses fatty acid oxidation and delays liver regeneration through the transcription factor PPAR.

After 70% partial hepatectomy (PHx), the metabolic pathways leading to hepatocyte lipid droplet accumulation during liver regeneration remain unclear. Aquaporin 5 (Aqp5) is an aquaporin that facilitates the transport of both water and hydrogen peroxide (H₂O₂). In this study, we observed delayed liver regeneration following PHx in Aqp5 knockout (Aqp5^-/-) mice. Considering the role of Aqp5 in H₂O₂ transport, we hypothesized that deficiency in Aqp5 may induce oxidative stress and hepatocyte injury. Through the measurement of reactive oxygen species (ROS) and redox-related indices, we observed significant alterations in ROS levels as well as malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) concentrations in regenerating livers lacking Aqp5 compared to wild-type controls. Oil Red O and 4-hydroxynonenal (4-HNE) staining results indicated that Aqp5 deficiency caused lipid accumulation during liver regeneration. The transcriptome sequencing results showed that the PPAR pathway is inhibited during the liver regeneration process in Aqp5 gene-knockout mice. The administration of the WY-14643 agonist, which targets the PPAR pathway, significantly mitigated delayed liver regeneration by enhancing hepatocyte proliferation and reducing lipid accumulation caused by Aqp5 deficiency. Our findings highlight the crucial role of Aqp5 in regulating H₂O₂ levels and lipid metabolism through the PPAR pathway during liver regeneration.