Abstract
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.
Highlights
Hepatitis B virus (HBV) infection frequently results in acute and chronic hepatitis, which could lead to liver cirrhosis and hepatocellular carcinoma (HCC).Approximately 350 million people worldwide are infected by HBV [1]
Pathway analysis of our collected HCC gene signatures from Encyclopedia of Hepatocellular Carcinoma genes Online 3 (EHCO3) indicates that up-regulated genes are mainly enriched in signaling, infection and cell cyclerelated pathways, whereas down-regulated genes are enriched in metabolism pathways related to lipid synthesis, glycolysis, and amino acid metabolism (Figure 1A–1B)
Down-regulation of enzymes might implicate that some metabolic reactions have been slowed down and resulted in the accumulation of upstream intermediates, such as glucose-6-phosphate (G-6-P) and 3-phosphoglycerate (3-PG), which could be used by pathways needed for HCC to proliferate [30, 31]
Summary
Hepatitis B virus (HBV) infection frequently results in acute and chronic hepatitis, which could lead to liver cirrhosis and hepatocellular carcinoma (HCC).Approximately 350 million people worldwide are infected by HBV [1]. Hepatitis B virus (HBV) infection frequently results in acute and chronic hepatitis, which could lead to liver cirrhosis and hepatocellular carcinoma (HCC). The risk of HCC increases more than 100-fold in HBV carriers with both obesity and diabetes, indicating the synergistic effects of metabolic factors and hepatitis [2, 3]. Four proteins originate from the HBV genome, including polymerase, surface antigen, core, and HBx proteins. HBx and core proteins are associated with HBV-related pathogenesis [4, 5]. The X gene encodes the X protein (HBx), which has transactivating properties and might be important in hepatic carcinogenesis. The core gene encodes the core nucleocapsid protein (important in viral packaging) [6]. In vitro studies suggest that core promoter mutations increase HBV replication [7]
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