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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

HH-F3 suppresses HBsAg, gluconeogenic enzyme gene expression, and the HBV DNA level in Hep3B/T2 and 1.3ES2 cells(A) Hep3B/T2 cells were treated with different concentrations of HH-F3 in serum-free DMEM medium for 48 h. HBsAg was determined by ELISA. Insulin was used as a positive control. (B–D) Cultured 1.3ES2 cells were treated with different concentrations of HH-F3 in serum-free DMEM medium for 48 h. The gluconeogenic enzyme genesG6Pase, PEPCK, and PGC-1α, as well as HBV mRNA expression, were measured by Q-RT PCR and normalized to β-actin. (E) HBV core protein levels were determined by Western blot analysis. (F) Q-RT PCR was used to detect wild-type HBV DNA in the medium of 1.3ES2 cells. *P < 0.05, **P < 0.01, ***P < 0.005 compared with the vehicle group (n = 3).
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Figure 5: HH-F3 suppresses HBsAg, gluconeogenic enzyme gene expression, and the HBV DNA level in Hep3B/T2 and 1.3ES2 cells(A) Hep3B/T2 cells were treated with different concentrations of HH-F3 in serum-free DMEM medium for 48 h. HBsAg was determined by ELISA. Insulin was used as a positive control. (B–D) Cultured 1.3ES2 cells were treated with different concentrations of HH-F3 in serum-free DMEM medium for 48 h. The gluconeogenic enzyme genesG6Pase, PEPCK, and PGC-1α, as well as HBV mRNA expression, were measured by Q-RT PCR and normalized to β-actin. (E) HBV core protein levels were determined by Western blot analysis. (F) Q-RT PCR was used to detect wild-type HBV DNA in the medium of 1.3ES2 cells. *P < 0.05, **P < 0.01, ***P < 0.005 compared with the vehicle group (n = 3).

Mentions: To evaluate whether HH-F3 might affect HBV gene expression, we used the Hep3B/T2 cell line, which can continuously secrete HBsAg into the culture medium, as our cell model. Treatment of HH-F3 for 48 h resulted in a dose-dependent suppression of HBsAg expression in Hep3B/T2 cells (Figure 5A). Next, we used the 1.3ES2 cell line, which is a subline of HepG2 cells, containing 1.3 copies of the entire HBV genome stably integrated into the HepG2 cell genome [34]. To explore whether HH-F3 could inhibit HBV gene expression via the regulation of PGC-1α, 1.3ES2 cells were treated with HH-F3 for 48 h. As a result, HH-F3 not only suppressed gluconeogenic enzyme G6Pase, PEPCK (Figure 5B) and coactivator PGC-1α gene expression (Figure 5C) but also suppressed HBV mRNA (Figure 5D) and core protein levels (Figure 5E) in 1.3ES2 cells. Additionally, treatment with HH-F3 significantly reduced HBV DNA replication in a dose-dependent manner in 1.3ES2 cells (Figure 5F). The synthetic compound HE-145 has been reported to inhibit HBV gene expression [35]; therefore, it was used as a positive control. These results indicate that HH-F3 inhibition of viral expression may be associated with gluconeogenesis machinery.


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)

HH-F3 suppresses HBsAg, gluconeogenic enzyme gene expression, and the HBV DNA level in Hep3B/T2 and 1.3ES2 cells(A) Hep3B/T2 cells were treated with different concentrations of HH-F3 in serum-free DMEM medium for 48 h. HBsAg was determined by ELISA. Insulin was used as a positive control. (B–D) Cultured 1.3ES2 cells were treated with different concentrations of HH-F3 in serum-free DMEM medium for 48 h. The gluconeogenic enzyme genesG6Pase, PEPCK, and PGC-1α, as well as HBV mRNA expression, were measured by Q-RT PCR and normalized to β-actin. (E) HBV core protein levels were determined by Western blot analysis. (F) Q-RT PCR was used to detect wild-type HBV DNA in the medium of 1.3ES2 cells. *P < 0.05, **P < 0.01, ***P < 0.005 compared with the vehicle group (n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 5: HH-F3 suppresses HBsAg, gluconeogenic enzyme gene expression, and the HBV DNA level in Hep3B/T2 and 1.3ES2 cells(A) Hep3B/T2 cells were treated with different concentrations of HH-F3 in serum-free DMEM medium for 48 h. HBsAg was determined by ELISA. Insulin was used as a positive control. (B–D) Cultured 1.3ES2 cells were treated with different concentrations of HH-F3 in serum-free DMEM medium for 48 h. The gluconeogenic enzyme genesG6Pase, PEPCK, and PGC-1α, as well as HBV mRNA expression, were measured by Q-RT PCR and normalized to β-actin. (E) HBV core protein levels were determined by Western blot analysis. (F) Q-RT PCR was used to detect wild-type HBV DNA in the medium of 1.3ES2 cells. *P < 0.05, **P < 0.01, ***P < 0.005 compared with the vehicle group (n = 3).
Mentions: To evaluate whether HH-F3 might affect HBV gene expression, we used the Hep3B/T2 cell line, which can continuously secrete HBsAg into the culture medium, as our cell model. Treatment of HH-F3 for 48 h resulted in a dose-dependent suppression of HBsAg expression in Hep3B/T2 cells (Figure 5A). Next, we used the 1.3ES2 cell line, which is a subline of HepG2 cells, containing 1.3 copies of the entire HBV genome stably integrated into the HepG2 cell genome [34]. To explore whether HH-F3 could inhibit HBV gene expression via the regulation of PGC-1α, 1.3ES2 cells were treated with HH-F3 for 48 h. As a result, HH-F3 not only suppressed gluconeogenic enzyme G6Pase, PEPCK (Figure 5B) and coactivator PGC-1α gene expression (Figure 5C) but also suppressed HBV mRNA (Figure 5D) and core protein levels (Figure 5E) in 1.3ES2 cells. Additionally, treatment with HH-F3 significantly reduced HBV DNA replication in a dose-dependent manner in 1.3ES2 cells (Figure 5F). The synthetic compound HE-145 has been reported to inhibit HBV gene expression [35]; therefore, it was used as a positive control. These results indicate that HH-F3 inhibition of viral expression may be associated with gluconeogenesis machinery.

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