Gluconeogenesis, lipogenesis, and HBV replication are commonly regulated by PGC-1α-dependent pathway
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Hong-Jhih Jhuang1,*, Wei-Hsiang Hsu2,*, Kuan-Ting Lin3, Shih-Lan Hsu4, Feng-Sheng Wang5, Chen-Kung Chou6, Kuen-Haur Lee8, Ann-Ping Tsou9, Jin-Mei Lai7, Sheau-Farn Yeh1, Chi-Ying F. Huang2,3,9
1Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan
2Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
3Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan
4Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
5Department of Chemical Engineering, National Chung Cheng University, Chiayi, Taiwan
6Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
7Department of Life Science, Fu-Jen Catholic University, New Taipei City, Taiwan
8Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
9Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan
*These authors have contributed equally to this work
Jin-Mei Lai, e-mail: [email protected]
Sheau-Farn Yeh, e-mail: [email protected]
Chi-Ying F. Huang, e-mail: [email protected]
Keywords: Graptopetalum paraguayense, HBV, Gluconeogenesis, Lipogenesis, PGC-1α
Received: November 04, 2014 Accepted: January 06, 2015 Published: February 03, 2015
PGC-1α, a major metabolic regulator of gluconeogenesis and lipogenesis, is strongly induced to coactivate Hepatitis B virus (HBV) gene expression in the liver of fasting mice. We found that 8-Br-cAMP and glucocorticoids synergistically induce PGC-1α and its downstream targets, including PEPCK and G6Pase. Also, HBV core promoter activity was synergistically enhanced by 8-Br-cAMP and glucocorticoids. Graptopetalum paraguayense (GP), a herbal medicine, is commonly used in Taiwan to treat liver disorders. Partially purified fraction of GP (named HH-F3) suppressed 8-Br-cAMP/glucocorticoid-induced G6Pase, PEPCK and PGC-1α expression and suppressed HBV core promoter activity. HH-F3 blocked HBV core promoter activity via inhibition of PGC-1α expression. Ectopically expressed PGC-1α rescued HH-F3-inhibited HBV surface antigen expression, HBV mRNA production, core protein levels, and HBV replication. HH-F3 also inhibited fatty acid synthase (FASN) expression and decreased lipid accumulation by down-regulating PGC-1α. Thus, HH-F3 can inhibit HBV replication, gluconeogenesis and lipogenesis by down-regulating PGC-1α. Our study indicates that targeting PGC-1α may be a therapeutic strategy for treatment of HBV infections. HH-F3 may have potential use for the treatment of chronic hepatitis B patients with associated metabolic syndrome.
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