Abstract 1132: Gluconeogenesis, lipogenesis, and HBV replication are commonly regulated by PGC-1α-dependent pathway

Abstract

Abstract Peroxisome proliferator-activated receptor-γ coactivator 1 (PGC-1α), a major metabolic regulator of gluconeogenesis and lipogenesis, is known to be strongly induced to coactivate HBV gene expression in the liver of fasting mice. In this study, we found that the combination of 8-Br-cAMP and glucocorticoids showed the synergistic induction of PGC-1α and its downstream gene expression, including the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Moreover, HBV corepromoter activity was synergistically enhanced by the combination of 8-Br-cAMP and glucocorticoid treatment. Graptopetalum paraguayense (GP), a herbal medicine, is commonly used in Taiwan to treat liver disorders. Here, we found that a partially purified fraction of GP (named HH-F3) dose dependently suppressed 8-Br-cAMP/glucocorticoid-induced G6Pase, PEPCKand PGC-1α expression as well as suppressed HBV core promoter activity. Additionally, HH-F3 blocked HBV core promoter activity via the inhibition of PGC-1α expression. The ectopic expression of PGC-1α effectively reversed the HH-F3-mediated inhibition of HBV core promoter activity.HH-F3-reduced HBV surface antigen expression, HBV mRNA production, core protein level, and HBV replication were drastically rescued by ectopically expressed PGC-1α. In addition, HH-F3 could also inhibit fatty acid synthase (FASN) expression as well as decrease lipid accumulation by the down-regulation of PGC-1α in human hepatocarcinoma cell lines. In conclusion, HH-F3 could inhibit HBV replication, gluconeogenesis, and lipogenesis through the down-regulation of PGC-1α. Our study indicates that targeting PGC-1α may be a novel therapeutic strategy for HBV infection. Together, HH-F3mighthave potential use for the treatment of chronic hepatitis B patients with associated metabolic syndrome. Citation Format: Wei-Hsiang Hsu, Hong-Jhih Jhuang, Chi-Ying Huang. Gluconeogenesis, lipogenesis, and HBV replication are commonly regulated by PGC-1α-dependent pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1132. doi:10.1158/1538-7445.AM2015-1132