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

ABSTRACT: Hypoxia-inducible factor (HIF)-1? and HIF-2? play an important role in liver fibrosis. von Hippel-Lindau protein (VHL), a key mediator of HIF-?, 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, normoxia-active HIF-?, and lentiviral vectors to silence HIF-?. The results showed that liver sections from fibrosis patients had a lower level of VHL and higher levels of HIF-1? and HIF-2? 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-1? plus HIF-2?. Normoxia-active HIF-1? or HIF-2? prevented the inhibitory effect of VHL on liver fibrosis, indicating that attenuating fibrosis via VHL is HIF-1?- and HIF-2?-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.

SUBMITTER: Wang J

PROVIDER: S-EPMC5253623 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Wang Jizhou J Lu Zhaoyang Z Xu Zhilin Z Tian Pei P Miao Hui H Pan Shangha S Song Ruipeng R Sun Xueying X Zhao Baolei B Wang Dawei D Ma Yong Y Song Xuan X Zhang Shugeng S Liu Lianxin L Jiang Hongchi H

Scientific reports 20170123

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 V ...[more]

PMID: 28112200

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Project description:BACKGROUND:PTEN loss contributes to the development of liver diseases including hepatic steatosis and both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The factors that influence the penetrance of these conditions are unclear. We explored the influence of sustained hypoxia signaling through co-deletion of Pten and Vhl in a murine model. METHODS:We used a CreER-linked Keratin 18 mouse model to conditionally delete Pten, Vhl or both in somatic cells of adult mice, evaluating the resultant tumors by histology and gene expression microarray. Existing sets of gene expression data for human HCC and CC were examined for pathways related to those observed in the murine tumors, and a cohort of human CC samples was evaluated for relationships between HIF-1? expression and clinical outcomes. RESULTS:Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl with the Keratin 18 promoter resulted in reduced steatosis and a reduced tumor burden that was characterized by a trabecular architecture similar to CC. Genes associated with hepatic steatosis were coordinately expressed in the human HCC dataset, while genes involved in hypoxia response were upregulated in tumors from the human CC dataset. HIF-1? expression and overall survival were examined in an independent cohort of human CC tumors with no statistical differences uncovered. CONCLUSION:Pten deletion in Keratin 18 expressing cells leads to aggressive tumor formation and widespread steatosis in mouse livers. Co-deletion of Vhl and Pten results in lower tumor burden with gene expression profiling suggesting a switch from a profile of lipid deposition to an expression profile more consistent with upregulation of the hypoxia response pathway. A relationship between tumor hypoxia signaling and altered hepatic steatotic response suggests that competing influences may alter tumor phenotypes.

Dataset Information

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

Publications

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

Similar Datasets

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