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

Jhuang HJ, Hsu WH, Lin KT, Hsu SL, Wang FS, Chou CK, Lee KH, Tsou AP, Lai JM, Yeh SF, Huang CY - Oncotarget (2015)

Bottom Line: We found that 8-Br-cAMP and glucocorticoids synergistically induce PGC-1α and its downstream targets, including PEPCK and G6Pase.HH-F3 also inhibited fatty acid synthase (FASN) expression and decreased lipid accumulation by down-regulating PGC-1α.HH-F3 may have potential use for the treatment of chronic hepatitis B patients with associated metabolic syndrome.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.

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.

No MeSH data available.


Related in: MedlinePlus

Pathway analysis of up- and down-regulated genes in hepatocellular carcinomaTwo network diagrams are presented here to illustrate the pathways enriched by up- and down-regulated genes, respectively. (A) Up-regulated genes were mainly enriched in signaling, infection, and cell cycle-related pathways, whereas (B) down-regulated genes were enriched only in metabolism pathways related to lipid synthesis, glycolysis, amino acid metabolism, and P450 metabolism. Each node represents a pathway, and the number of genes in the pathway determines the size of the node. The larger the pathway, the bigger the size of the node is. The P-value from pathway enrichment analysis determines the redness of the balls. The lower the p-value, the redder the node is. The thickness of the lines between nodes in the network represents the number of genes that the two pathways have in common. (C) The blueprint of metabolism pathways adapted from KEGG to illustrate dysregulated reactions based on EHCO3 (green lines: reactions whose enzymes are down-regulated; red lines: reactions whose enzymes are up-regulated). Purple lines are reactions whose enzymes in HCC could be reversed from down-regulation to up-regulation by GP/HH-F3, whereas blue lines are reactions whose enzyme expression levels could be suppressed by GP/HH-F3. (D) Huh7 cells were treated with 30% DMSO GP extracts and HH-F3 for 24 h, respectively. Western blot shows the effects after GP/HH-F3 treatment for HK2, PKM2, pyruvate dehydrogenase complex (PDH), phosphorylated PDH (p-PDH) and PDHK with GAPDH used as a control. (E) GP/HH-F3 could influence the TCA cycle via down-regulation of phosphorylated PDH, but GP/HH-F3 could not affect other molecules in the TCA cycle. A possible mechanism describing how GP/HH-F3 restores dysregulated glycolysis. Glucose-6-phosphate (G-6-P), 3-phosphoglycerate (3-PG), and phosphoenolpyruvate (PEP) are key intermediates in glycolysis.
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Figure 1: Pathway analysis of up- and down-regulated genes in hepatocellular carcinomaTwo network diagrams are presented here to illustrate the pathways enriched by up- and down-regulated genes, respectively. (A) Up-regulated genes were mainly enriched in signaling, infection, and cell cycle-related pathways, whereas (B) down-regulated genes were enriched only in metabolism pathways related to lipid synthesis, glycolysis, amino acid metabolism, and P450 metabolism. Each node represents a pathway, and the number of genes in the pathway determines the size of the node. The larger the pathway, the bigger the size of the node is. The P-value from pathway enrichment analysis determines the redness of the balls. The lower the p-value, the redder the node is. The thickness of the lines between nodes in the network represents the number of genes that the two pathways have in common. (C) The blueprint of metabolism pathways adapted from KEGG to illustrate dysregulated reactions based on EHCO3 (green lines: reactions whose enzymes are down-regulated; red lines: reactions whose enzymes are up-regulated). Purple lines are reactions whose enzymes in HCC could be reversed from down-regulation to up-regulation by GP/HH-F3, whereas blue lines are reactions whose enzyme expression levels could be suppressed by GP/HH-F3. (D) Huh7 cells were treated with 30% DMSO GP extracts and HH-F3 for 24 h, respectively. Western blot shows the effects after GP/HH-F3 treatment for HK2, PKM2, pyruvate dehydrogenase complex (PDH), phosphorylated PDH (p-PDH) and PDHK with GAPDH used as a control. (E) GP/HH-F3 could influence the TCA cycle via down-regulation of phosphorylated PDH, but GP/HH-F3 could not affect other molecules in the TCA cycle. A possible mechanism describing how GP/HH-F3 restores dysregulated glycolysis. Glucose-6-phosphate (G-6-P), 3-phosphoglycerate (3-PG), and phosphoenolpyruvate (PEP) are key intermediates in glycolysis.

Mentions: Pathway analysis of our collected HCC gene signatures from EHCO3 indicates that up-regulated genes are mainly enriched in signaling, infection and cell cycle-related pathways, whereas down-regulated genes are enriched in metabolism pathways related to lipid synthesis, glycolysis, and amino acid metabolism (Figure 1A–1B). The up-regulated genes are mostly factors modulating signaling pathways in tumor cells to maintain the production of necessary materials for proliferation, and many of them are drug targets such as mitogen-activated protein kinase (MAPK). On the other hand, the down-regulated genes are mainly involved in lipid, amino acids, cytochrome P450, and glycolysis-related pathways. 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].


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

Jhuang HJ, Hsu WH, Lin KT, Hsu SL, Wang FS, Chou CK, Lee KH, Tsou AP, Lai JM, Yeh SF, Huang CY - Oncotarget (2015)

Pathway analysis of up- and down-regulated genes in hepatocellular carcinomaTwo network diagrams are presented here to illustrate the pathways enriched by up- and down-regulated genes, respectively. (A) Up-regulated genes were mainly enriched in signaling, infection, and cell cycle-related pathways, whereas (B) down-regulated genes were enriched only in metabolism pathways related to lipid synthesis, glycolysis, amino acid metabolism, and P450 metabolism. Each node represents a pathway, and the number of genes in the pathway determines the size of the node. The larger the pathway, the bigger the size of the node is. The P-value from pathway enrichment analysis determines the redness of the balls. The lower the p-value, the redder the node is. The thickness of the lines between nodes in the network represents the number of genes that the two pathways have in common. (C) The blueprint of metabolism pathways adapted from KEGG to illustrate dysregulated reactions based on EHCO3 (green lines: reactions whose enzymes are down-regulated; red lines: reactions whose enzymes are up-regulated). Purple lines are reactions whose enzymes in HCC could be reversed from down-regulation to up-regulation by GP/HH-F3, whereas blue lines are reactions whose enzyme expression levels could be suppressed by GP/HH-F3. (D) Huh7 cells were treated with 30% DMSO GP extracts and HH-F3 for 24 h, respectively. Western blot shows the effects after GP/HH-F3 treatment for HK2, PKM2, pyruvate dehydrogenase complex (PDH), phosphorylated PDH (p-PDH) and PDHK with GAPDH used as a control. (E) GP/HH-F3 could influence the TCA cycle via down-regulation of phosphorylated PDH, but GP/HH-F3 could not affect other molecules in the TCA cycle. A possible mechanism describing how GP/HH-F3 restores dysregulated glycolysis. Glucose-6-phosphate (G-6-P), 3-phosphoglycerate (3-PG), and phosphoenolpyruvate (PEP) are key intermediates in glycolysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480716&req=5

Figure 1: Pathway analysis of up- and down-regulated genes in hepatocellular carcinomaTwo network diagrams are presented here to illustrate the pathways enriched by up- and down-regulated genes, respectively. (A) Up-regulated genes were mainly enriched in signaling, infection, and cell cycle-related pathways, whereas (B) down-regulated genes were enriched only in metabolism pathways related to lipid synthesis, glycolysis, amino acid metabolism, and P450 metabolism. Each node represents a pathway, and the number of genes in the pathway determines the size of the node. The larger the pathway, the bigger the size of the node is. The P-value from pathway enrichment analysis determines the redness of the balls. The lower the p-value, the redder the node is. The thickness of the lines between nodes in the network represents the number of genes that the two pathways have in common. (C) The blueprint of metabolism pathways adapted from KEGG to illustrate dysregulated reactions based on EHCO3 (green lines: reactions whose enzymes are down-regulated; red lines: reactions whose enzymes are up-regulated). Purple lines are reactions whose enzymes in HCC could be reversed from down-regulation to up-regulation by GP/HH-F3, whereas blue lines are reactions whose enzyme expression levels could be suppressed by GP/HH-F3. (D) Huh7 cells were treated with 30% DMSO GP extracts and HH-F3 for 24 h, respectively. Western blot shows the effects after GP/HH-F3 treatment for HK2, PKM2, pyruvate dehydrogenase complex (PDH), phosphorylated PDH (p-PDH) and PDHK with GAPDH used as a control. (E) GP/HH-F3 could influence the TCA cycle via down-regulation of phosphorylated PDH, but GP/HH-F3 could not affect other molecules in the TCA cycle. A possible mechanism describing how GP/HH-F3 restores dysregulated glycolysis. Glucose-6-phosphate (G-6-P), 3-phosphoglycerate (3-PG), and phosphoenolpyruvate (PEP) are key intermediates in glycolysis.
Mentions: Pathway analysis of our collected HCC gene signatures from EHCO3 indicates that up-regulated genes are mainly enriched in signaling, infection and cell cycle-related pathways, whereas down-regulated genes are enriched in metabolism pathways related to lipid synthesis, glycolysis, and amino acid metabolism (Figure 1A–1B). The up-regulated genes are mostly factors modulating signaling pathways in tumor cells to maintain the production of necessary materials for proliferation, and many of them are drug targets such as mitogen-activated protein kinase (MAPK). On the other hand, the down-regulated genes are mainly involved in lipid, amino acids, cytochrome P450, and glycolysis-related pathways. 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].

Bottom Line: We found that 8-Br-cAMP and glucocorticoids synergistically induce PGC-1α and its downstream targets, including PEPCK and G6Pase.HH-F3 also inhibited fatty acid synthase (FASN) expression and decreased lipid accumulation by down-regulating PGC-1α.HH-F3 may have potential use for the treatment of chronic hepatitis B patients with associated metabolic syndrome.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan.

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.

No MeSH data available.


Related in: MedlinePlus