Possible Involvement of Hepatitis B Virus Infection of Hepatocytes in the Attenuation of Apoptosis in Hepatic Stellate Cells

Sasaki, Reina; Nakamura, Masato; Nakamoto, Shingo; Haga, Yuki; Wu, Shuang; Shirasawa, Hiroshi; Yokosuka, Osamu

doi:10.1371/journal.pone.0146314

Cited by 19 publications

(28 citation statements)

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“…(43) Very recently, c-Jun has been linked to the apoptosis of HSCs. (33) In agreement, induced apoptosis as a result of neddylation inhibition is concomitant with augmented levels of c-Jun, and, more important, c-Jun silencing protects LX-2 cells from MLN4924-induced apoptosis. c-Jun accumulation after neddylation inhibition is most probably a consequence of the fact that c-Jun was shown to be degraded by neddylated cullins.…”

Section: Discussionmentioning

confidence: 68%

“…This approach is advantageous, considering some recent evidence highlighting that HSC reversion, even though it can lead to resolution of fibrosis, can result in higher responsiveness of reverted HSCs to recurring fibrogenesis stimulus . Very recently, c‐Jun has been linked to the apoptosis of HSCs . In agreement, induced apoptosis as a result of neddylation inhibition is concomitant with augmented levels of c‐Jun, and, more important, c‐Jun silencing protects LX‐2 cells from MLN4924‐induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Deregulated neddylation in liver fibrosis

et al. 2016

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Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. Even though the ubiquitin-like post-translational modification of neddylation, that conjugates Nedd8 to specific targets, is aberrant in many pathologies, its relevance in liver fibrosis remained unexplored. Our results show deregulated neddylation in clinical fibrosis and both in mouse bileduct ligation (BDL)-and carbon tetrachloride (CCl 4 )-induced fibrosis. Importantly, neddylation inhibition, by using the pharmacological inhibitor MLN4924 reduced liver injury, apoptosis, inflammation and fibrosis by targeting different hepatic cell types. On one hand, increased neddylation was associated with augmented caspase-3-activity in bile acid-induced apoptosis in mouse hepatocytes whereas neddylation inhibition ameliorated apoptosis through reduction of the † Joint Corresponding authors: María Luz Martínez-Chantar, CIC bioGUNE, Ed. 801A Parque Tecnológico de Bizkaia, 48160 Derio, Bizkaia, Spain. mlmartinez@cicbiogune.es; Tel: +34-944-061318; Fax: +34-944-061301. Teresa Cardoso Delgado, CIC bioGUNE, Ed. 801A Parque Tecnológico de Bizkaia, 48160 Derio, Bizkaia, Spain. tcardoso@cicbiogune.es; Tel: +34-944-061318; Fax: +34-944-061301. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript expression of the Cxcl1 and Ccl2 chemokines. On the other hand, chemokine receptors and cytokines, usually induced in activated macrophages, were reduced after neddylation inhibition in mouse Kupffer cells. Under these circumstances, decreased hepatocyte cell death and inflammation after neddylation inhibition could partly account for reduction of hepatic stellate cell activation. In spite of this, we provide evidence that augmented neddylation characterizes activated hepatic stellate cells suggesting that neddylation inhibition could be important for resolving liver fibrosis by directly targeting these fibrogenic cells. Indeed, neddylation inhibition in activated hepatic stellate cells induces apoptosis in a process partly mediated by the accumulation of c-Jun, whose cullin-mediated degradation is impaired under these circumstances.Conclusions-Overall, neddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. KeywordsFibrosis; Nedd8; Post-translational modification; Kupffer cell; Hepatic stellate cell Liver fibrosis is a global health problem and a critical process in liver disease as well as a major risk factor for progression to cirrhosis and hepatocellular carcinoma (HCC), one of the commonest and deadliest solid organ tumors (1). The progression and resolution of fibrosis is a complex process involving the interaction between parenchymal and nonparenchymal cells where chronic hepatocyte death often acts as a triggering event (2). For example, during cholestasis, a condition where bile efflux is disrupted, the accumulation of bile acids (BA) in the liver directly activates a signaling network in hepatocytes that promotes in...

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Deregulated neddylation in liver fibrosis

et al. 2016

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“…Huh7, HepG2 and HepG2.2.15 were previously reported [11, 12]. Huh6 and PLC/PRF/5 were purchased from the National Institutes of Biomedical Innovation, Health and Nutrition JCRB Cell Bank (Ibaraki, Osaka, Japan).…”

Section: Methodsmentioning

confidence: 99%

Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines

et al. 2017

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BackgroundDespite recent advances in treatment strategies, it is still difficult to cure patients with hepatocellular carcinoma (HCC). Sorafenib is the only approved multiple kinase inhibitor for systemic chemotherapy in patients with advanced HCC. The majority of advanced HCC patients are resistant to sorafenib. The mechanisms of sorafenib resistance are still unknown.MethodsThe expression of molecules involved in the mitogen-activated protein kinase (MAPK) signaling pathway in human hepatoma cell lines was examined in the presence or absence of sorafenib. Apoptosis of human hepatoma cells treated with sorafenib was investigated, and the expression of Jun proto-oncogene (c-Jun) was measured.ResultsThe expression and phosphorylation of c-Jun were enhanced in human hepatoma cell lines after treatment with sorafenib. Inhibiting c-Jun enhanced sorafenib-induced apoptosis. The overexpression of c-Jun impaired sorafenib-induced apoptosis. The expression of osteopontin, one of the established AP-1 target genes, was enhanced after treatment with sorafenib in human hepatoma cell lines.ConclusionsThe protein c-Jun plays a role in sorafenib resistance in human hepatoma cell lines. The modulation and phosphorylation of c-Jun could be a new therapeutic option for enhancing responsiveness to sorafenib. Modulating c-Jun may be useful for certain HCC patients with sorafenib resistance.

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“…These results suggested that upregulation of ARRDC3 in hepatocytes might inhibit hepatic stellate cell apoptosis, resulting in the progression of liver fibrosis. Although we also tried to detect apoptosis of LX-2 cells by apoptosis marker Annexin V [26], we did not see any differences more clearly (data not shown). Further studies will be needed.…”

Section: Conditioned Media From Endogenous Arrdc3-knockdown-hepg2 Enhmentioning

confidence: 82%

“…Human hepatoma cell lines (HepG2 and Huh7), hepatic stellate cell line LX-2 and human pancreatic cancer MIAPaCa-2 cells were maintained in Roswell Park Memorial Institute medium (RPMI 1640) (Sigma, St. Louis, MO, USA) supplemented with 1-10% fetal bovine serum, penicillin (100 U/mL) and streptomycin (100 μg/mL) at 5% CO2 and 37°C. HepG2, Huh7 and MIAPaCa-2 cells were purchased from the Japanese Collection of Research Bioresources Cell Bank (Ibaraki, Osaka, Japan) [26,51]. LX-2 cells, spontaneously immortalized cells, were kindly provided by Prof. Scott L. Friedman, Mount Sinai Medical School, NY, USA [52].…”

Section: Cell Lines and Reagentsmentioning

confidence: 99%

Possible association of arrestin domain-containing protein 3 and progression of non-alcoholic fatty liver disease

Ogawa¹,

Higuchi²,

Takahashi³

et al. 2019

Int. J. Med. Sci.

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909 I In nt te er rn na at ti io on na al l J Jo ou ur rn na al l o of f M Me ed di ic ca al l S Sc ci ie en nc ce es s 2019; 16(7): 909-921. AbstractThe prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing worldwide. Several effective drugs for these diseases are now in development and under clinical trials. It is important to reveal the mechanism of the development of NAFLD and NASH. We investigated the role of arrestin domain-containing protein 3 (ARRDC3), which is linked to obesity in men and regulates body mass, adiposity and energy expenditure, in the progression of NAFLD and NASH. We performed knockdown of endogenous ARRDC3 in human hepatocytes and examined the inflammasome-associated gene expression by real-time PCR-based array. We also examined the effect of conditioned medium from endogenous ARRDC3-knockdown-hepatocytes on the apoptosis of hepatic stellate cells. We observed that free acids enhanced the expression of ARRDC3 in hepatocytes. Knockdown of ARRDC3 could lead to the inhibition of inflammasome-associated gene expression in hepatocytes. We also observed that conditioned medium from endogenous ARRDC3-knockdown-hepatocytes enhances the apoptosis of hepatic stellate cells. ARRDC3 has a role in the progression of NAFLD and NASH and is one of the targets for the development of the effective treatment of NAFLD and NASH.

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Possible Involvement of Hepatitis B Virus Infection of Hepatocytes in the Attenuation of Apoptosis in Hepatic Stellate Cells

Cited by 19 publications

References 53 publications

Deregulated neddylation in liver fibrosis

Deregulated neddylation in liver fibrosis

Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines

Possible association of arrestin domain-containing protein 3 and progression of non-alcoholic fatty liver disease

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