Hypoxia induces the activation of human hepatic stellate cells LX‐2 through TGF‐β signaling pathway

Shi, Yue-Feng; Fong, Chi-Chun; Zhang, Qi; Cheung, Pik-Yuen; Tzang, Chi-Hung; Wu, Rudolf S.S.; Yang, Mengsu

doi:10.1016/j.febslet.2006.12.010

Cited by 76 publications

(63 citation statements)

References 31 publications

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“…However, how copper regulates the fibrotic pathway is still unknown. It has been reported that hypoxia-induced activation of hepatic stellate cells occurs through the TGF-␤ signaling pathway, and hypoxia-inducible factor (HIF)-1␣ gene expression was significantly up-regulated in cultured stellate cells in response to hypoxia (Shi et al, 2007). HIF-1 is a ubiquitously expressed transcriptional master regulator of many genes involved in mammalian oxygen homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Tetrathiomolybdate Protects against Bile Duct Ligation-Induced Cholestatic Liver Injury and Fibrosis

Song¹,

Song²,

Barve³

et al. 2008

J Pharmacol Exp Ther

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Section: Discussionmentioning

confidence: 99%

Tetrathiomolybdate Protects against Bile Duct Ligation-Induced Cholestatic Liver Injury and Fibrosis

Song¹,

Song²,

Barve³

et al. 2008

J Pharmacol Exp Ther

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“…The complete blunting of hepcidin to all inflammatory cytokines and BMPs in SMAD4-knockout mice (43) suggests that decreased SMAD4 may be a central mechanism of hepcidin repression. Hypoxia and reactive oxygen species have been implicated in both the induction and the inhibition of receptor SMADs (2,35,38,46) and SMAD4 nuclear localization (19). Furthermore, inhibitory SMADs and a number of E3 ubiquitin ligases are implicated in this process because they target SMAD4 for proteolytic degradation (44,45).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia inhibits hepcidin expression in HuH7 hepatoma cells via decreased SMAD4 signaling

Chaston

Matak

Pourvali

et al. 2011

American Journal of Physiology-Cell Physiology

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Hepcidin negatively regulates systemic iron homeostasis in response to inflammation and elevated serum iron. Conversely, hepcidin expression is diminished in response to hypoxia, oxidative stress, and increased erythropoietic demand, though the molecular intermediates involved are incompletely understood. To address this, we have investigated hypoxic hepcidin regulation in HuH7 hepatoma cells either cultured alone or cocultured with activated THP-1 macrophages. HuH7 hepcidin mRNA expression was determined using quantitative polymerase chain reaction (Q-PCR). Hepcidin promoter activity was measured using luciferase reporter constructs containing a 0.9 kb fragment of the wild-type human hepcidin promoter, and constructs containing mutations in bone morphogenetic protein (BMP)/SMAD4, signal transducer and activator of transcription 3 (STAT3), CCAAT/enhancer-binding protein (C/EBP), and E-box-responsive elements. Hepatic expression of bone morphogenetic proteins BMP2 and BMP6 and the BMP inhibitor noggin was determined using Q-PCR, and the protein expression of hemojuvelin (HJV), pSMAD 1/5/8, and SMAD4 was determined by western blotting. Following exposure to hypoxia or H2O2, hepcidin mRNA expression and promoter activity increased in HuH7 cells monocultures but were decreased in HuH7 cells cocultured with THP-1 macrophages. This repression was attenuated by mutation of the BMP/SMAD4-response element, suggesting that modulation of SMAD signaling mediated the response to hypoxia. No changes in hepatocyte BMP2, BMP6 or noggin mRNA, or protein expression of HJV or pSMAD 1/5/8 were detected. However, treatment with hypoxia caused a marked decrease in nuclear and cytosolic SMAD4 protein and SMAD4 mRNA expression in cocultured HuH7 cells. Together these data indicate that hypoxia represses hepcidin expression through inhibition of BMP/ SMAD signaling.hepatocytes; macrophages; oxidative stress THE LIVER-EXPRESSED PEPTIDE hepcidin (23) has emerged as a major regulator of systemic iron homeostasis. During inflammation, hepcidin is secreted into the serum, where it blocks iron release from duodenal enterocytes and reticuloendothelial macrophages, causing hypoferremia (8,10,12,20,36). Hepcidin transcription is also sensitive to systemic iron levels, body iron stores, erythropoietic factors, and hypoxia in vivo (14,29,33), and the regulated production and release of the peptide plays a central role in the maintenance of iron homeostasis. This is supported by the inappropriate regulation of hepcidin expression seen in transgenic animal models of iron overload that lack functional genes for HFE, hemojuvelin (HJV), or transferrin receptor 2 (1, 6, 28, 31).The systemic and intracellular mechanisms that underlie negative regulation of hepcidin by hypoxia and oxidative stress are incompletely understood. Studies in rodent models have demonstrated dramatic effects of hypoxia on iron homeostasis: increased intestinal iron absorption (24, 25, 30, 37) and decreased expression of hepcidin (24,29,32). The molecular intermediates that signa...

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“…There are some published papers reporting that MMP-9 expression is directly or indirectly regulated by HIF-1. [24][25][26] Therefore, we hypothesized that increased HIF-1 transcription activity in normal cells in the liver contributes to MMP-9 production induced by tumor cell inoculation. Intravenous administration of pshHIF-1a was effective in reducing the expression of MMP-9 after tumor inoculation, which indicates that HIF-1 expression in tumor cells and normal cells in the liver might play an important role in MMP-9 production.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of tumor cell growth in the liver by RNA interference-mediated suppression of HIF-1α expression in tumor cells and hepatocytes

2008

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Hypoxia-inducible factor-1 (HIF-1) is a ubiquitously expressed oxygen-regulated transcription factor composed of a and b subunits. HIF-1 activates transcription of various genes including those involved in metastatic tumor growth. In the present study, HIF-1a expression in tumor-bearing mouse liver was examined after inoculation of tumor cells into portal vein. We found that tumor-bearing liver showed greatly increased HIF-1a expression. Plasmid DNA (pDNA) expressing short hairpin RNA targeting HIF-1a (pshHIF-1a) was effective in suppressing protein expression of HIF-1a in vitro. Intravenous injection of pshHIF-1a by hydrodynamics-based procedure reduced the HIF-1a protein expression in both normal and tumor cells and tumor cell number in the liver. Pre-injection of pshHIF-1a to mice, by which pDNA was delivered only to liver cells, not to tumor cells, was also effective in reducing the number of tumor cells inoculated 3 days after pDNA injection. These findings indicate that HIF-1a expression is increased in normal liver cells as well as tumor cells, and HIF-1a expression plays an important role in tumor progression. Use of the RNA interference (RNAi) of HIF-1 is an effective strategy for inhibiting tumor cell growth, and both tumor and normal cells can be the target for RNAi-based anticancer treatment.

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Hypoxia induces the activation of human hepatic stellate cells LX‐2 through TGF‐β signaling pathway

Cited by 76 publications

References 31 publications

Tetrathiomolybdate Protects against Bile Duct Ligation-Induced Cholestatic Liver Injury and Fibrosis

Tetrathiomolybdate Protects against Bile Duct Ligation-Induced Cholestatic Liver Injury and Fibrosis

Hypoxia inhibits hepcidin expression in HuH7 hepatoma cells via decreased SMAD4 signaling

Inhibition of tumor cell growth in the liver by RNA interference-mediated suppression of HIF-1α expression in tumor cells and hepatocytes

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