Epimorphin, a morphogenic protein, induces proteases in rodent hepatocytes through NF-κB

Miura, Kouichi; Yoshino, Ryutaro; Hirai, Yohei; Goto, Takashi; Ohshima, Shigetoshi; Mikami, Koji; Yoneyama, Kazuo; Watanabe, Dai; Sato, Mitsuru; Senoo, Haruki; Kodama, Yuzo; Osawa, Yosuke; Brenner, David A.; Watanabe, Sumio

doi:10.1016/j.jhep.2007.07.024

Cited by 17 publications

(29 citation statements)

References 48 publications

(63 reference statements)

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“…However, in models of liver regeneration, Epim also appears to increase later in HSCs highlighting a potential role during the recovery phase of tissue repair [21]–[23]. In line with this, a feature of EPIM in both renal and liver fibrosis is its ability to induce protease expression favoring collagen degradation and resolution of fibrosis [22], [24], [25]. Although this provides clues of EPIM's role in modulating the ECM in fibrosis the mechanisms by which it acts and is regulated are less clear.…”

Section: Introductionmentioning

confidence: 70%

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Epimorphin Alters the Inhibitory Effects of SOX9 on Mmp13 in Activated Hepatic Stellate Cells

et al. 2014

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Background and AimsLiver fibrosis is a major cause of morbidity and mortality. It is characterised by excessive extracellular matrix (ECM) deposition from activated hepatic stellate cells (HSCs). Although potentially reversible, treatment remains limited. Understanding how ECM influences the pathogenesis of the disease may provide insight into novel therapeutic targets for the disease. The extracellular protein Epimorphin (EPIM) has been implicated in tissue repair mechanisms in several tissues, partially, through its ability to manipulate proteases. In this study, we have identified that EPIM modulates the ECM environment produced by activated hepatic stellate cells (HSCs), in part, through down-regulation of pro-fibrotic Sex-determining region Y-box 9 (SOX9).MethodsInfluence of EPIM on ECM was investigated in cultured primary rat HSCs. Activated HSCs were treated with recombinant EPIM or SOX9 siRNA. Core fibrotic factors were evaluated by immunoblotting, qPCR and chromatin immunoprecipitation (ChIP).ResultsDuring HSC activation EPIM became significantly decreased in contrast to pro-fibrotic markers SOX9, Collagen type 1 (COL1), and α- Smooth muscle actin (α-SMA). Treatment of activated HSCs with recombinant EPIM caused a reduction in α-SMA, SOX9, COL1 and Osteopontin (OPN), while increasing expression of the collagenase matrix metalloproteinase 13 (MMP13). Sox9 abrogation in activated HSCs increased EPIM and MMP13 expression.ConclusionThese data provide evidence for EPIM and SOX9 functioning by mutual negative feedback to regulate attributes of the quiescent or activated state of HSCs. Further understanding of EPIM's role may lead to opportunities to modulate SOX9 as a therapeutic avenue for liver fibrosis.

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Section: Introductionmentioning

confidence: 70%

“…Studies have suggested Epim facilitates the recovery phase following liver injury [22]. It has been associated with resolution of fibrosis in both kidney and liver by inducing protease expression to cause ECM degradation [22], [24].…”

Section: Resultsmentioning

confidence: 99%

Epimorphin Alters the Inhibitory Effects of SOX9 on Mmp13 in Activated Hepatic Stellate Cells

et al. 2014

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“…11,24 To inhibit NF- κ B activation, a recombinant adenovirus expressing inhibitor of NF- κ B (I κ B) super-repressor was used. 11,21,24 …”

Section: Methodsmentioning

confidence: 99%

“…Blots were incubated with antibody for tissue inhibitor of metalloproteinase-1 (TIMP1; R&D Systems) or IL-1R–associated kinase M (IRAK-M; Cell Signaling Technology Inc, Danvers, MA). 11,24 …”

Section: Methodsmentioning

confidence: 99%

Toll-Like Receptor 9 Promotes Steatohepatitis by Induction of Interleukin-1β in Mice

et al. 2010

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BACKGROUND & AIMS Development of nonalcoholic steatohepatitis (NASH) involves the innate immune system and is mediated by Kupffer cells and hepatic stellate cells (HSCs). Toll-like receptor 9 (TLR9) is a pattern recognition receptor that recognizes bacteria-derived cytosine phosphate guanine (CpG)–containing DNA and activates innate immunity. We investigated the role of TLR9 signaling and the inflammatory cytokine interleukin-1β (IL-1β) in steatohepatitis, fibrosis, and insulin resistance. METHODS Wild-type (WT), TLR9−/−, IL-1 receptor (IL-1R)−/−, and MyD88−/− mice were fed a choline-deficient amino acid-defined (CDAA) diet for 22 weeks and then assessed for steatohepatitis, fibrosis, and insulin resistance. Lipid accumulation and cell death were assessed in isolated hepatocytes. Kupffer cells and HSCs were isolated to assess inflammatory and fibrogenic responses, respectively. RESULTS The CDAA diet induced NASH in WT mice, characterized by steatosis, inflammation, fibrosis, and insulin resistance. TLR9−/− mice showed less steatohepatitis and liver fibrosis than WT mice. Among inflammatory cytokines, IL-1β production was suppressed in TLR9−/− mice. Kupffer cells produced IL-1β in response to CpG oligodeoxynucleotide. IL-1β but not CpG-oligodeoxynucleotides, increased lipid accumulation in hepatocytes. Lipid accumulation in hepatocytes led to nuclear factor-κB inactivation, resulting in cell death in response to IL-1β. IL-1β induced fibrogenic responses in HSCs, including secretion of tissue inhibitor of metalloproteinase-1. IL-1R−/− mice had reduced steatohepatitis and fibrosis, compared with WT mice. Mice deficient in MyD88, an adaptor molecule for TLR9 and IL-1R signaling, also had reduced steatohepatitis and fibrosis. TLR9−/−, IL-1R−/−, and MyD88−/− mice had less insulin resistance than WT mice on the CDAA diet. CONCLUSIONS In a mouse model of NASH, TLR9 signaling induces production of IL-1β by Kupffer cells, leading to steatosis, inflammation, and fibrosis.

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“…While ZW10 binds to syntaxin-18 and play a role in vesicle transport between Golgi and the endoplasmic reticulum (33), it is also known as a mitotic checkpoint protein, controlling attachment of microtubules to kinetochores of chromosomes in Drosophila (34). Syntaxin-2, which is localized on plasma membrane and involved in post-Golgi transport, has also been identified as an extracellular molecule playing a role in morphogenesis of epithelial organs (35) including liver (36). Overexpression of syntaxin-2 in the mouse mammary gland promotes alveolar hyperplasia and mammary adenocarcinoma (5).…”

Section: Discussionmentioning

confidence: 99%

Expression of α-taxilin in hepatocellular carcinoma correlates with growth activity and malignant potential of the tumor

Tomiya¹

2010

Int J Oncol

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Abstract. The membrane traffic system has been recognized to be involved in carcinogenesis and tumor progression in several types of tumors. ·-taxilin is a newly identified membrane traffic-related molecule, and its up-regulation has been reported in embryonic and malignant tissues of neural origin. In the present study, we analyzed the expression of ·-taxilin in relation to clinicopathological features of hepatocellular carcinomas (HCC) and proliferative activity of the tumor determined by proliferating cell nuclear antigen labeling index (PCNA-LI). Twenty-nine surgically resected nodules of HCC (8 well-, 11 moderately-, and 10 poorlydifferentiated) were studied. Fifteen cases showed 'strong staining', while 14 cases showed 'weak staining' for ·-taxilin. A significantly higher expression of ·-taxilin was observed in less-differentiated (p=0.005), and more invasive (p=0.016) HCCs. The 'strong staining' group showed significantly higher PCNA-LI than the 'weak staining' group (the medians of PCNA-LI were 59.4% vs. 14.4%, p<0.0001). We also evaluated the expression of ·-taxilin in hepatoma cell lines (PLC/PRF/5, Hep G2 and HuH-6) in association with cell proliferation. The expression levels of ·-taxilin protein were correlated with their growth rates. In conclusion, the expression of the ·-taxilin protein was related with an increased proliferative activity and a less-differentiated histological grade of HCC. ·-taxilin may be involved in cell proliferation of HCC, and its expression can be a marker of malignant potential of HCC.

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Epimorphin, a morphogenic protein, induces proteases in rodent hepatocytes through NF-κB

Cited by 17 publications

References 48 publications

Epimorphin Alters the Inhibitory Effects of SOX9 on Mmp13 in Activated Hepatic Stellate Cells

Epimorphin Alters the Inhibitory Effects of SOX9 on Mmp13 in Activated Hepatic Stellate Cells

Toll-Like Receptor 9 Promotes Steatohepatitis by Induction of Interleukin-1β in Mice

Expression of α-taxilin in hepatocellular carcinoma correlates with growth activity and malignant potential of the tumor

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