Geranylgeranylacetone decreases the production of hepatitis B virus-related antigen by comprehensive downregulation of mRNA transcription activity.
ER stress
Geranylgeranylacetone
HBV enhancer
HBV promoter
Hepatitis B virus
Journal
Journal of gastroenterology and hepatology
ISSN: 1440-1746
Titre abrégé: J Gastroenterol Hepatol
Pays: Australia
ID NLM: 8607909
Informations de publication
Date de publication:
Jul 2021
Jul 2021
Historique:
revised:
06
12
2020
received:
17
08
2019
accepted:
24
12
2020
pubmed:
5
1
2021
medline:
15
12
2021
entrez:
4
1
2021
Statut:
ppublish
Résumé
Elimination of hepatitis B virus (HBV) is infrequently achieved with current therapies. Therefore, more effective anti-HBV therapy is needed. We previously reported that geranylgeranylacetone (GGA) showed anti-hepatitis C virus activity in human hepatoma cells. In this study, we examined the anti-HBV activity of GGA. We used HepG2.2.15.7 cells, PXB cells infected with HBV, Huh7 cells transfected with linear HBV, and PLC/PRF/5 cells as HBV-infected hepatocyte models. After GGA treatment, HBV-related antigen was measured by chemiluminescent immunoassay. HBV-related mRNA was examined by Northern blot. cccDNA and endoplasmic reticulum stress markers were measured by real-time polymerase chain reaction. The activities of HBV promoters and enhancer regions were examined using luciferase vectors. After GGA treatment, hepatitis B surface antigen and hepatitis B e antigen secretion was decreased in all HBV-infected hepatocyte models. HBV-related mRNA was also decreased by GGA treatment, although cccDNA levels were not affected. Additionally, the activity of HBV S1 and S2 promoter region and Enhancer 1/Enhancer 2/core promoter region was reduced by GGA treatment. The mRNA expression of the main transcription factors, hepatocyte nuclear factor 3 and 4 and CCAAT/enhancer binding protein, was also decreased. Further, the expression levels of endoplasmic reticulum stress markers were increased by GGA treatment, which reflected the change in HBV-related antigen secretion. Geranylgeranylacetone treatment reduces HBV-related protein levels by suppressing comprehensive downregulation of HBV promoter and enhancer activity, which might be caused by decreased hepatic transcription factor expression. GGA treatment may enhance anti-HBV effects in combination with other therapies.
Sections du résumé
BACKGROUND AND AIM
OBJECTIVE
Elimination of hepatitis B virus (HBV) is infrequently achieved with current therapies. Therefore, more effective anti-HBV therapy is needed. We previously reported that geranylgeranylacetone (GGA) showed anti-hepatitis C virus activity in human hepatoma cells. In this study, we examined the anti-HBV activity of GGA.
METHODS
METHODS
We used HepG2.2.15.7 cells, PXB cells infected with HBV, Huh7 cells transfected with linear HBV, and PLC/PRF/5 cells as HBV-infected hepatocyte models. After GGA treatment, HBV-related antigen was measured by chemiluminescent immunoassay. HBV-related mRNA was examined by Northern blot. cccDNA and endoplasmic reticulum stress markers were measured by real-time polymerase chain reaction. The activities of HBV promoters and enhancer regions were examined using luciferase vectors.
RESULTS
RESULTS
After GGA treatment, hepatitis B surface antigen and hepatitis B e antigen secretion was decreased in all HBV-infected hepatocyte models. HBV-related mRNA was also decreased by GGA treatment, although cccDNA levels were not affected. Additionally, the activity of HBV S1 and S2 promoter region and Enhancer 1/Enhancer 2/core promoter region was reduced by GGA treatment. The mRNA expression of the main transcription factors, hepatocyte nuclear factor 3 and 4 and CCAAT/enhancer binding protein, was also decreased. Further, the expression levels of endoplasmic reticulum stress markers were increased by GGA treatment, which reflected the change in HBV-related antigen secretion.
CONCLUSIONS
CONCLUSIONS
Geranylgeranylacetone treatment reduces HBV-related protein levels by suppressing comprehensive downregulation of HBV promoter and enhancer activity, which might be caused by decreased hepatic transcription factor expression. GGA treatment may enhance anti-HBV effects in combination with other therapies.
Substances chimiques
Diterpenes
0
Hepatitis B Surface Antigens
0
RNA, Messenger
0
Transcription Factors
0
geranylgeranylacetone
S8S8451A4O
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1979-1987Informations de copyright
© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.
Références
Lee WM. Hepatitis B virus infection. N. Engl. J. Med. 1997; 337: 1733-1745.
Shepard CW, Simard EP, Finelli L, Fiore AE, Bell BP. Hepatitis B virus infection: epidemiology and vaccination. Epidemiol. Rev. 2006; 28: 112-125.
Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 2012; 30: 2212-2219.
Trepo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet (London, England) 2014; 384: 2053-2063.
Llansola M, Cantero JL, Hita-Yanez E et al. Progressive reduction of sleep time and quality in rats with hepatic encephalopathy caused by portacaval shunts. Neuroscience 2012; 201: 199-208.
Zoulim F, Locarnini S. Optimal management of chronic hepatitis B patients with treatment failure and antiviral drug resistance. Liver Int. 2013; 33: 116-124.
Locarnini S, Hatzakis A, Chen DS, Lok A. Strategies to control hepatitis B: public policy, epidemiology, vaccine and drugs. J. Hepatol. 2015; 62: S76-S86.
Murakami M, Oketani K, Fujisaki H, Wakabayashi T, Ohgo T. Antiulcer effect of geranylgeranylacetone, a new acyclic polyisoprenoid on experimentally induced gastric and duodenal ulcers in rats. Arzneimittelforschung 1981; 31: 799-804.
Hirakawa T, Rokutan K, Nikawa T, Kishi K. Geranylgeranylacetone induces heat shock proteins in cultured guinea pig gastric mucosal cells and rat gastric mucosa. Gastroenterology 1996; 111: 345-357.
Sakabe M, Shiroshita-Takeshita A, Maguy A et al. Effects of a heat shock protein inducer on the atrial fibrillation substrate caused by acute atrial ischaemia. Cardiovasc. Res. 2008; 78: 63-70.
Fudaba Y, Ohdan H, Tashiro H et al. Geranylgeranylacetone, a heat shock protein inducer, prevents primary graft nonfunction in rat liver transplantation. Transplantation 2001; 72: 184-189.
Sakai I, Tanaka T, Osawa S, Hashimoto S, Nakaya K. Geranylgeranylacetone used as an antiulcer agent is a potent inducer of differentiation of various human myeloid leukemia cell lines. Biochem. Biophys. Res. Commun. 1993; 191: 873-879.
Okada S, Yabuki M, Kanno T et al. Geranylgeranylacetone induces apoptosis in HL-60 cells. Cell Struct. Funct. 1999; 24: 161-168.
Takeshita S, Ichikawa T, Taura N et al. Geranylgeranylacetone has anti-hepatitis C virus activity via activation of mTOR in human hepatoma cells. J. Gastroenterol. 2012; 47: 195-202.
Iwamoto M, Cai D, Sugiyama M et al. Functional association of cellular microtubules with viral capsid assembly supports efficient hepatitis B virus replication. Sci. Rep. 2017; 7: 10620.
Ishida Y, Yamasaki C, Yanagi A et al. Novel robust in vitro hepatitis B virus infection model using fresh human hepatocytes isolated from humanized mice. Am. J. Pathol. 2015; 185: 1275-1285.
Gunther S, Li BC, Miska S, Kruger DH, Meisel H, Will H. A novel method for efficient amplification of whole hepatitis B virus genomes permits rapid functional analysis and reveals deletion mutants in immunosuppressed patients. J. Virol. 1995; 69: 5437-5444.
Akazawa Y, Isomoto H, Matsushima K et al. Endoplasmic reticulum stress contributes to Helicobacter pylori VacA-induced apoptosis. PLoS ONE 2013; 8: e82322.
Akazawa Y, Cazanave S, Mott JL et al. Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis. J. Hepatol. 2010; 52: 586-593.
Dias-Teixeira KL, Calegari-Silva TC, Medina JM et al. Emerging role for the PERK/eIF2α/ATF4 in human cutaneous leishmaniasis. Sci. Rep. 2017; 7: 17074.
Kim DH, Kang HS, Kim KH. Roles of hepatocyte nuclear factors in hepatitis B virus infection. World J. Gastroenterol. 2016; 22: 7017-7029.
Senoo T, Sasaki R, Akazawa Y et al. Geranylgeranylacetone attenuates fibrogenic activity and induces apoptosis in cultured human hepatic stellate cells and reduces liver fibrosis in carbon tetrachloride-treated mice. BMC Gastroenterol. 2018; 18: 34.
Vachirayonsti T, Ho KW, Yang D, Yan B. Suppression of the pregnane X receptor during endoplasmic reticulum stress is achieved by down-regulating hepatocyte nuclear factor-4α and up-regulating liver-enriched inhibitory protein. Toxicol. Sci. 2015; 144: 382-392.
Tseng TC, Liu CJ, Yang HC et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology 2012; 142: 1140-1149.
Terrault NA, Bzowej NH, Chang KM et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology 2016; 63: 261-283.
Vannice JL, Levinson AD. Properties of the human hepatitis B virus enhancer: position effects and cell-type nonspecificity. J. Virol. 1988; 62: 1305-1313.
Nawa T, Ishida H, Tatsumi T et al. Interferon-α suppresses hepatitis B virus enhancer II activity via the protein kinase C pathway. Virology 2012; 432: 452-459.
Lopez-Cabrera M, Letovsky J, Hu KQ, Siddiqui A. Transcriptional factor C/EBP binds to and transactivates the enhancer element II of the hepatitis B virus. Virology 1991; 183: 825-829.
Fukai K, Takada S, Yokosuka O, Saisho H, Omata M, Koike K. Characterization of a specific region in the hepatitis B virus enhancer I for the efficient expression of X gene in the hepatic cell. Virology 1997; 236: 279-287.
Endo S, Hiramatsu N, Hayakawa K et al. Geranylgeranylacetone, an inducer of the 70-kDa heat shock protein (HSP70), elicits unfolded protein response and coordinates cellular fate independently of HSP70. Mol. Pharmacol. 2007; 72: 1337-1348.
Hasegawa J, Morishita N, Seki T, Hashida N, Kanazawa T, Sato A. Effect of meals in healthy adult administered Selbex. Syokakika. 1987; 7: 740-752.
Walter RM Jr, Gold EM, Michas CA, Ensinck JW. Portal and peripheral vein concentrations of insulin and glucagon after arginine infusion in morbidly obese subjects. Metab.: Clin. Exp. 1980; 29: 1037-1040.
Oda H, Miyake H, Iwata T, Kusumoto K, Rokutan K, Tashiro S. Geranylgeranylacetone suppresses inflammatory responses and improves survival after massive hepatectomy in rats. J. Gastrointest. Surg. 2002; 6: 464-472 discussion 73.
Fudaba Y, Tashiro H, Ohdan H et al. Prevention of warm ischemic injury in rat liver transplantation by geranylgeranylacetone. Transplant. Proc. 2000; 32: 1615-1616.