Mechanism of SENP1-Mediated Regulation of Liver Sinusoidal Endothelial Cells to Promote Regeneration Via the HIF-1α Signaling Pathway

Abstract

Background and aims: Liver sinusoidal endothelial cells (LSECs) play a critical role in liver regeneration, but the specific molecular mechanism underlying this process remains unclear. Previous studies have shown that Sentrin/SUMO-specific protease 1 (SENP1) maintains the differentiation state of LSECs and promotes their proliferation under hypoxic conditions; however, the role of SENP1 in promoting liver regeneration by regulating LSECs is still unknown.

Methods: We employed a 70% hepatectomy (PHx) mouse model to explore the molecular mechanism underlying SENP1 regulation of LSECs and to observe the promotion of liver regeneration via the HIF-1α signaling pathway in vitro and in vivo.

Results: First, we found that the liver regeneration began on the first day after hepatectomy, while SENP1 expression in liver tissue was significantly upregulated. After SENP1 downregulation, the expression of Ki-67 and von Willebrand factor (vWF) in liver tissue decreased, as did the rate of liver regeneration. Second, in vitro, the proliferation activity of LSECs with SENP1 overexpression increased, and fenestration was better maintained. After co-culturing hepatocytes with LSECs that overexpress SENP1, an EdU assay showed that hepatocyte proliferation ability increased significantly. However, the opposite occurred when either a SENP1 or a HIF-1α inhibitor was used. In vivo, we observed that SENP1 can activate the VEGF/VEGFR2/Id1 signaling axis, upregulating the expression of VEGF and HGF through the HIF-1α signaling pathway, thus promoting hepatocyte proliferation and angiogenesis.

Conclusions: SENP1 may promote liver regeneration by regulating LSECs dependent on the HIF-1α signaling pathway.

Keywords: Hypoxia-inducible transcription factor-1α; Liver regeneration; Liver sinusoidal endothelial cells; Partial hepatectomy; Sentrin/sumo-specific protease 1.