Hepatic angiocrine HGF weakens liver fibrogenesis by modulating the PDK1/Akt axis

Introduction Hepatocyte growth factor (HGF) is a complete hepatic mitogen and is thought to play a role in liver fibrogenesis and hepatocarcinogenesis. Liver sinusoidal endothelial cells (LSEC) can recruit inflammatory cells by releasing angiocrine signals to produce HGF in the process of liver fibrosis and cirrhosis, but the precise contributions of HGF from LSEC to liver fibrosis remain elucidated.

Methods To study the effects of hepatic angiocrine HGF on liver fibrogenesis, Stab2-Cretg HGFfl/fl (HGFLSEC-KO) mice, in which HGF is specifically knocked out in LSEC, were used. These mice were repeatedly injected with carbon tetrachloride (CCl4) for six weeks. After onset of cirrhosis, we analyzed liver-to-body weight ratio kinetics, immunohistochemistry, Western blot and RT-PCR for fibrotic markers, HGF/c-MET-related pathway components and cell cycle-associated genes.

Results We found that HGF-LSEC-KO mice showed no difference in relative liver weights after early-stage CCl4 treatment. However, HGF-LSEC-KO mice exhibited higher expression levels of collagen 1A1 and alpha-SMA, and hepatocyte proliferation was significantly impaired in HGF-LSEC-KO mice. Furthermore, LSEC-specific HGF deficiency deactivated the PDK1/Akt pathway, while hepatic angiocrine HGF did not alter immune cell infiltration. Aquaporin-4 (AQP4) was identified to be highly expressed in HGF-deficient LSEC by RNA sequencing, which could be confirmed by consecutive expression analysis.

Conclusion The hepatic angiocrine HGF signaling pathway plays a crucial role in early stages of liver fibrogenesis and is essential not only for liver recovery during fibrogenesis, but also for liver and even whole organism growth.

Publication History

Article published online:
18 January 2023