Phosphoenolpyruvate carboxykinaseandglucose-6-phosphatase are required for steroidogenesis in testicular leydig cells

Seung Won Ahn, Gil Tae Gang, Surendar Tadi, Balachandar Nedumaran, Yong Deuk Kim, Ji Hoon Park, Gi Ryang Kweon, Seung Hoi Koo, Keesook Lee, Ryun Sup Ahn, Yong Hyeon Yim, Chul Ho Lee, Robert Harris, Hueng Sik Choi

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Abstract

Cyclic AMP (cAMP) induces steroidogenic enzyme gene expression and stimulates testosterone production in Leydig cells. Phosphoenolpyruvate carboxykinase (PEPCK) is expressed in Leydig cells, but its role has not been defined. In this study, we found that PEPCK and glucose-6-phosphatase (Glc-6-Pase) are increased significantly following cAMP treatment of mouse Leydig cells. Moreover, cAMP treatment increased recruitment of the cAMP-response element-binding transcription factor and decreased recruitment of the corepressor DAX-1 on the pepck promoter. Furthermore, cAMP induced an increase in ATP that correlated with a decrease in phospho- AMP-activated protein kinase (AMPK). In contrast, knockdown or inhibition of PEPCK decreased ATP and increased phospho- AMPK. Treatment with an AMPK activator or overexpression of the constitutively active form of AMPK inhibited cAMP-induced steroidogenic enzyme promoter activities and gene expression. Liver receptor homolog-1 (LRH-1) was involved in cAMP-induced steroidogenic enzyme gene expression but was inhibited by AMPK activation in Leydig cells. Additionally, inhibition or knockdown of PEPCK and Glc-6-Pase decreased cAMP-mediated induction of steroidogenic enzyme gene expression and steroidogenesis. Finally, pubertal mouse (8-week-old) testes and human chorionic gonadotropin-induced prepubertal mouse testes showed increased PEPCK and Glc-6-Pase gene expression. Taken together, these results suggest that induction of PEPCK and Glc-6-Pase by cAMP plays an important role in Leydig cell steroidogenesis.

Original languageEnglish
Pages (from-to)41875-41887
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number50
DOIs
StatePublished - Dec 7 2012

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Phosphoenolpyruvate
Leydig Cells
Phosphoric Monoester Hydrolases
Cyclic AMP
AMP-Activated Protein Kinases
Glucose-6-Phosphatase
Gene expression
Gene Expression
Phosphoenolpyruvate Carboxykinase (ATP)
Testis
Enzymes
Adenosine Triphosphate
Co-Repressor Proteins
Enzyme Induction
Enzyme activity
Response Elements
Chorionic Gonadotropin
Liver
Testosterone
Transcription Factors

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Ahn, S. W., Gang, G. T., Tadi, S., Nedumaran, B., Kim, Y. D., Park, J. H., ... Choi, H. S. (2012). Phosphoenolpyruvate carboxykinaseandglucose-6-phosphatase are required for steroidogenesis in testicular leydig cells. Journal of Biological Chemistry, 287(50), 41875-41887. https://doi.org/10.1074/jbc.M112.421552

Phosphoenolpyruvate carboxykinaseandglucose-6-phosphatase are required for steroidogenesis in testicular leydig cells. / Ahn, Seung Won; Gang, Gil Tae; Tadi, Surendar; Nedumaran, Balachandar; Kim, Yong Deuk; Park, Ji Hoon; Kweon, Gi Ryang; Koo, Seung Hoi; Lee, Keesook; Ahn, Ryun Sup; Yim, Yong Hyeon; Lee, Chul Ho; Harris, Robert; Choi, Hueng Sik.

In: Journal of Biological Chemistry, Vol. 287, No. 50, 07.12.2012, p. 41875-41887.

Research output: Contribution to journalArticle

Ahn, SW, Gang, GT, Tadi, S, Nedumaran, B, Kim, YD, Park, JH, Kweon, GR, Koo, SH, Lee, K, Ahn, RS, Yim, YH, Lee, CH, Harris, R & Choi, HS 2012, 'Phosphoenolpyruvate carboxykinaseandglucose-6-phosphatase are required for steroidogenesis in testicular leydig cells', Journal of Biological Chemistry, vol. 287, no. 50, pp. 41875-41887. https://doi.org/10.1074/jbc.M112.421552
Ahn, Seung Won ; Gang, Gil Tae ; Tadi, Surendar ; Nedumaran, Balachandar ; Kim, Yong Deuk ; Park, Ji Hoon ; Kweon, Gi Ryang ; Koo, Seung Hoi ; Lee, Keesook ; Ahn, Ryun Sup ; Yim, Yong Hyeon ; Lee, Chul Ho ; Harris, Robert ; Choi, Hueng Sik. / Phosphoenolpyruvate carboxykinaseandglucose-6-phosphatase are required for steroidogenesis in testicular leydig cells. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 50. pp. 41875-41887.
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abstract = "Cyclic AMP (cAMP) induces steroidogenic enzyme gene expression and stimulates testosterone production in Leydig cells. Phosphoenolpyruvate carboxykinase (PEPCK) is expressed in Leydig cells, but its role has not been defined. In this study, we found that PEPCK and glucose-6-phosphatase (Glc-6-Pase) are increased significantly following cAMP treatment of mouse Leydig cells. Moreover, cAMP treatment increased recruitment of the cAMP-response element-binding transcription factor and decreased recruitment of the corepressor DAX-1 on the pepck promoter. Furthermore, cAMP induced an increase in ATP that correlated with a decrease in phospho- AMP-activated protein kinase (AMPK). In contrast, knockdown or inhibition of PEPCK decreased ATP and increased phospho- AMPK. Treatment with an AMPK activator or overexpression of the constitutively active form of AMPK inhibited cAMP-induced steroidogenic enzyme promoter activities and gene expression. Liver receptor homolog-1 (LRH-1) was involved in cAMP-induced steroidogenic enzyme gene expression but was inhibited by AMPK activation in Leydig cells. Additionally, inhibition or knockdown of PEPCK and Glc-6-Pase decreased cAMP-mediated induction of steroidogenic enzyme gene expression and steroidogenesis. Finally, pubertal mouse (8-week-old) testes and human chorionic gonadotropin-induced prepubertal mouse testes showed increased PEPCK and Glc-6-Pase gene expression. Taken together, these results suggest that induction of PEPCK and Glc-6-Pase by cAMP plays an important role in Leydig cell steroidogenesis.",
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AU - Gang, Gil Tae

AU - Tadi, Surendar

AU - Nedumaran, Balachandar

AU - Kim, Yong Deuk

AU - Park, Ji Hoon

AU - Kweon, Gi Ryang

AU - Koo, Seung Hoi

AU - Lee, Keesook

AU - Ahn, Ryun Sup

AU - Yim, Yong Hyeon

AU - Lee, Chul Ho

AU - Harris, Robert

AU - Choi, Hueng Sik

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N2 - Cyclic AMP (cAMP) induces steroidogenic enzyme gene expression and stimulates testosterone production in Leydig cells. Phosphoenolpyruvate carboxykinase (PEPCK) is expressed in Leydig cells, but its role has not been defined. In this study, we found that PEPCK and glucose-6-phosphatase (Glc-6-Pase) are increased significantly following cAMP treatment of mouse Leydig cells. Moreover, cAMP treatment increased recruitment of the cAMP-response element-binding transcription factor and decreased recruitment of the corepressor DAX-1 on the pepck promoter. Furthermore, cAMP induced an increase in ATP that correlated with a decrease in phospho- AMP-activated protein kinase (AMPK). In contrast, knockdown or inhibition of PEPCK decreased ATP and increased phospho- AMPK. Treatment with an AMPK activator or overexpression of the constitutively active form of AMPK inhibited cAMP-induced steroidogenic enzyme promoter activities and gene expression. Liver receptor homolog-1 (LRH-1) was involved in cAMP-induced steroidogenic enzyme gene expression but was inhibited by AMPK activation in Leydig cells. Additionally, inhibition or knockdown of PEPCK and Glc-6-Pase decreased cAMP-mediated induction of steroidogenic enzyme gene expression and steroidogenesis. Finally, pubertal mouse (8-week-old) testes and human chorionic gonadotropin-induced prepubertal mouse testes showed increased PEPCK and Glc-6-Pase gene expression. Taken together, these results suggest that induction of PEPCK and Glc-6-Pase by cAMP plays an important role in Leydig cell steroidogenesis.

AB - Cyclic AMP (cAMP) induces steroidogenic enzyme gene expression and stimulates testosterone production in Leydig cells. Phosphoenolpyruvate carboxykinase (PEPCK) is expressed in Leydig cells, but its role has not been defined. In this study, we found that PEPCK and glucose-6-phosphatase (Glc-6-Pase) are increased significantly following cAMP treatment of mouse Leydig cells. Moreover, cAMP treatment increased recruitment of the cAMP-response element-binding transcription factor and decreased recruitment of the corepressor DAX-1 on the pepck promoter. Furthermore, cAMP induced an increase in ATP that correlated with a decrease in phospho- AMP-activated protein kinase (AMPK). In contrast, knockdown or inhibition of PEPCK decreased ATP and increased phospho- AMPK. Treatment with an AMPK activator or overexpression of the constitutively active form of AMPK inhibited cAMP-induced steroidogenic enzyme promoter activities and gene expression. Liver receptor homolog-1 (LRH-1) was involved in cAMP-induced steroidogenic enzyme gene expression but was inhibited by AMPK activation in Leydig cells. Additionally, inhibition or knockdown of PEPCK and Glc-6-Pase decreased cAMP-mediated induction of steroidogenic enzyme gene expression and steroidogenesis. Finally, pubertal mouse (8-week-old) testes and human chorionic gonadotropin-induced prepubertal mouse testes showed increased PEPCK and Glc-6-Pase gene expression. Taken together, these results suggest that induction of PEPCK and Glc-6-Pase by cAMP plays an important role in Leydig cell steroidogenesis.

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