title: Luteolin Inhibits Hepatitis B Virus Replication through Extracellular Signal-Regulated Kinase-Mediated Down-Regulation of Hepatocyte Nuclear Factor 4α Expression.
abstract: Whether luteolin inhibits HBV replication has not been validated and the underlying mechanism of which has never been elucidated. In this study, we show that luteolin reduces HBV DNA replication in HepG2.2.15 cells. Luteolin effectively inhibited the expression of hepatocyte nuclear factor 4α (HNF4α) and its binding to the HBV promoters in HepG2.2.15 cells. While the extracellular signal-regulated kinase (ERK) was activated by luteolin, inhibition of ERK abolished luteolin-induced HNF4α suppression. Consistently, blocking ERK attenuated the anti-HBV activity of luteolin. In a HBV replication mouse model, luteolin decreased the levels of HBsAg, HBeAg, HBV DNA replication intermediates, and the HBsAg and HBcAg expression. Taken together, our results validated the anti-HBV activity of luteolin in both in vitro and in vivo studies and established a signaling cascade consisting of ERK and HNF4α for inhibition of HBV replication by luteolin, which may be exploited for clinical application of luteolin for anti-HBV therapy.
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu 610041, China.|Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu 610041, China.
authors.forename: Lang
authors.initials: L
authors.lastname: Bai
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu 610041, China.|Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu 610041, China.
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Nong
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu 610041, China.|Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu 610041, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu 610041, China.|Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu 610041, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu 610041, China.|Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu 610041, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Yan
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu 610041, China.|Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu 610041, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Shang
authors.affiliation: Department of Forensic Pathology, Medical School of Basic and Forensic Sciences, Sichuan University , Chengdu 610041, China.
authors.forename: Feijun
authors.initials: F
authors.lastname: Huang
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute , 2425 Ridgecrest Dr. SE, Albuquerque, New Mexico 87108, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University , Chengdu 610041, China.|Division of Infectious Diseases, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu 610041, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
mesh_terms: D000818:Animals; D017209:Apoptosis; D015139:Blotting, Southern; D015153:Blotting, Western; D049109:Cell Proliferation; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006515:Hepatitis B virus / Q000187:drug effects*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047311:Luteolin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases; D047311:Luteolin
keywords: extracellular signal-regulated kinase; flavonoid; hepatitis B virus; hepatocyte nuclear factor 4α; replication