Reduction of hepatic fibrosis by overexpression of von Hippel–Lindau protein in experimental models of chronic liver disease

Abstract

Hypoxia-inducible factor (HIF)-1α and HIF-2α play an important role in liver fibrosis. von Hippel-Lindau protein (VHL), a key mediator of HIF-α, regulates fibrosis in an organ-and cell-specific way. In this study, human liver samples were collected from hepatitis C-, alcoholic-, and cholestatic-associated fibrotic and healthy individuals. Two mouse models of liver fibrosis were established: bile duct ligation and carbon tetrachloride injection. We constructed adenovirus vectors to overexpress VHL, normoxiaactive HIF-α, and lentiviral vectors to silence HIF-α. The results showed that liver sections from fibrosis patients had a lower level of VHL and higher levels of HIF-1α and HIF-2α compared with healthy sections, a finding which was confirmed in mice. Overexpression of VHL attenuated liver fibrosis, downregulated fibrogenic genes, and inhibited liver inflammation, apoptosis, and angiogenesis. Overexpression of VHL was more successful at inhibiting fibrosis compared with silencing HIF-1α plus HIF-2α. Normoxia-active HIF-1α or HIF-2α prevented the inhibitory effect of VHL on liver fibrosis, indicating that attenuating fibrosis via VHL is HIF-1α-and HIF-2α-dependent to some extent. In addition, overexpression of VHL inhibited mouse hepatic stellate cells activation and proliferation and promoted apoptosis. Taken together, VHL may be considered a new target to inhibit liver fibrosis.

Loss of Prolyl-Hydroxylase 1 Protects against Biliary Fibrosis via Attenuated Activation of Hepatic Stellate Cells

“…43 Previous studies have highlighted the significance of hypoxia in liver fibrosis and, more specifically, delineated a profibrotic role of the HIFs in its development. 8,16 Indeed, hypoxia levels are reportedly increased in fibrotic liver tissue, 8 and interference with HIF-1a and HIF-2a stabilization by forced expression of von Hippel-Lindau protein attenuates hepatic fibrosis in mice. 16 At first glance, it might thus appear paradoxical that global deletion of PHD1, which reportedly enhances hepatocellular HIF-2a (and to a lesser extent HIF-1a) levels, 18 has opposite effects.…”

“…8,16 Indeed, hypoxia levels are reportedly increased in fibrotic liver tissue, 8 and interference with HIF-1a and HIF-2a stabilization by forced expression of von Hippel-Lindau protein attenuates hepatic fibrosis in mice. 16 At first glance, it might thus appear paradoxical that global deletion of PHD1, which reportedly enhances hepatocellular HIF-2a (and to a lesser extent HIF-1a) levels, 18 has opposite effects. However, the present study reveals that loss of PHD1 was not accompanied by an increase of HIF-1a protein levels in HSCs.…”

“…The three PHD enzymes exert specific and nonredundant functions and are implicated in various pathologic disorders characterized by hypoxia. 13,14 The expression of HIF-1a increases gradually with the severity of liver fibrosis, 15,16 and the significance of HIF-1a in the pathogenesis of liver fibrosis has been well documented. 8,16 Specific functions of the HIF-PHD enzymes in this context are, by contrast, widely unknown.…”

The Role of Vascular Endothelial Growth Factor in Systemic Sclerosis

“…HIF and VEGF-A have been implicated in a number of fibrosing diseases including graft versus host disease, hepatic fibrosis and idiopathic pulmonary fibrosis (IPF) [75][76][77][78][79][80][81][82].…”

Inhibition of GSK‐3β induces AP‐1‐mediated osteopontin expression to promote cholestatic liver fibrosis

“…Six-week-old C57BL/6 mice were used in all experiments and were purchased from Shanghai Shanhai Laboratory Animal Center (Shanghai, China). All mice underwent BDL, which was previously described (15,16). The test group was injected by intraperitoneal route every 3 d with 25 mg/g SB216763 (Sigma-Adrich, Shanghai, China) diluted in DMSO; the first injection was performed 2 h prior to surgery.…”