RESUMEN
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.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/virología , Replicación del ADN/fisiología , Virus de la Hepatitis B/fisiología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/virología , Factores de Transcripción/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Crassulaceae/química , ADN Viral/genética , ADN Viral/metabolismo , Dexametasona/farmacología , Regulación Neoplásica de la Expresión Génica , Gluconeogénesis , Células Hep G2 , Antígenos de Superficie de la Hepatitis B/biosíntesis , Antígenos de Superficie de la Hepatitis B/genética , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/metabolismo , Humanos , Lipogénesis , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Extractos Vegetales/farmacología , Transducción de Señal , Factores de Transcripción/biosíntesis , Factores de Transcripción/genéticaRESUMEN
Helioxanthin and analogues have been demonstrated to suppress gene expression of human hepatitis B virus. In the continuous attempt to optimize antiviral activity, various structural motifs were grafted on the helioxanthin scaffold. Many such analogues were synthesized and evaluated for their anti-hepatitis B virus activity. Structure-activity relationships of these helioxanthin derivatives are also discussed. Among these new compounds, 15 exhibits the highest activity against HBV (EC50=0.06 µM). This compound can suppress viral surface antigen and DNA expression. Furthermore, viral RNA is also diminished while the core promoter is deactivated upon treatment by 15. A plausible working mechanism is postulated. Our results establish helioxanthin lignans as potent anti-HBV agents with unique mode of action. Since their antiviral mechanism is distinct from current nucleoside/nucleotide drugs, helioxanthin lignans constitute a potentially new class of anti-HBV agents for combination therapy.