Betulinic acid-mediated inhibitory effect on hepatitis B virus by suppression of manganese superoxide dismutase expression.
The betulinic acid (BetA) purified from Pulsatilla chinensis (PC) has been found to have selective inhibitory effects on hepatitis B virus (HBV). In hepatocytes from HBV-transgenic mice, we showed that BetA substantially inhibited HBV replication by downregulation of manganese superoxide dismutase (SOD2) expression, with subsequent reactive oxygen species generation and mitochondrial dysfunction. Also, the HBV X protein (HBx) is suppressed and translocated into the mitochondria followed by cytochrome c release. Further investigation revealed that SOD2 expression was suppressed by BetA-induced cAMP-response element-binding protein dephosphorylation at Ser133, which subsequently prevented SOD2 transcription through the cAMP-response element-binding protein-binding motif on the SOD2 promoter. SOD2 overexpression abolished the inhibitory effect of BetA on HBV replication, whereas SOD2 knockdown mimicked this effect, indicating that BetA-mediated HBV clearance was due to modulation of the mitochondrial redox balance. This observation was further confirmed in HBV-transgenic mice, where both BetA and PC crude extracts suppressed SOD2 expression, with enhanced reactive oxygen species generation in liver tissues followed by substantial HBV clearance. We conclude that BetA from PC could be a good candidate for anti-HBV drug development.
Internal Medicine of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. dachun927@hotmail.com
Dachun
D
Yao
Huawen
H
Li
Yulan
Y
Gou
Haimou
H
Zhang
Athanasios G
AG
Vlessidis
Haiyan
H
Zhou
Nicholaos P
NP
Evmiridis
Zhengxiang
Z
Liu
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002470:Cell Survival; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D006515:Hepatitis B virus / Q000187:drug effects* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D008957:Models, Genetic; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D031946:Pulsatilla / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects; D000094062:Betulinic Acid
D000998:Antiviral Agents; D017362:Cyclic AMP Response Element-Binding Protein; D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species; D014315:Triterpenes; D013482:Superoxide Dismutase; D000094062:Betulinic Acid