Fasting-induced hepatic production of DHEA is regulated by PGC-1α, ERRα, and HNF4α

Linda L. Grasfeder, Stephanie Gaillard, Stephen R. Hammes, Olga Ilkayeva, Christopher B. Newgard, Richard B. Hochberg, Mary A. Dwyer, Ching Yi Chang, Donald P. McDonnell

Research output: Contribution to journalArticle

Abstract

The transcriptional coactivator peroxisome proliferator-activated receptor-γcoactivator (PGC)-1α is involved in the coordinate induction of changes in gene expression in the liver that enable a homeostatic response to alterations in metabolic state, environmental cues, and nutrient availability. In exploring the specific pathways under PGC-1αregulation in the liver, we have made the surprising observation that this coactivator can induce the expression of CYP11A1 and CYP17A1, key rate-limiting enzymes involved in the initial steps of steroidogenesis. Both of these enzymes function to produce C19-steroids, converting cholesterol into pregnenolone, and then to dehydroepiandrosterone (DHEA). Estrogen-related receptor (ERR)-α mediates PGC-1α's induction of CYP11A1 and binds within the first intron of the CYP11A1 gene. Both ERR-α and hepatocyte nuclear factor-4α are required for PGC-1α-mediated induction of CYP17A1, and specific binding sites for these receptors have been identified in the regulatory regions of this gene. The potential physiological significance of these observations was highlighted in rats where fasting induced hepatic expression of PGC-1αand CYP17A1 and was associated with an increase in hepatic levels of DHEA. These data suggest that DHEA could be playing a role as an intracellular signaling molecule involved in modulating hepatic activity in response to fasting conditions.

Original languageEnglish (US)
Pages (from-to)1171-1182
Number of pages12
JournalMolecular Endocrinology
Volume23
Issue number8
DOIs
StatePublished - Aug 1 2009
Externally publishedYes

Fingerprint

Dehydroepiandrosterone
Cholesterol Side-Chain Cleavage Enzyme
Fasting
Liver
Estrogen Receptors
Hepatocyte Nuclear Factor 4
Pregnenolone
Peroxisome Proliferator-Activated Receptors
Nucleic Acid Regulatory Sequences
Enzymes
Regulator Genes
Introns
Cues
Steroids
Binding Sites
Cholesterol
ERRalpha estrogen-related receptor
Gene Expression
Food
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Grasfeder, L. L., Gaillard, S., Hammes, S. R., Ilkayeva, O., Newgard, C. B., Hochberg, R. B., ... McDonnell, D. P. (2009). Fasting-induced hepatic production of DHEA is regulated by PGC-1α, ERRα, and HNF4α. Molecular Endocrinology, 23(8), 1171-1182. https://doi.org/10.1210/me.2009-0024

Fasting-induced hepatic production of DHEA is regulated by PGC-1α, ERRα, and HNF4α. / Grasfeder, Linda L.; Gaillard, Stephanie; Hammes, Stephen R.; Ilkayeva, Olga; Newgard, Christopher B.; Hochberg, Richard B.; Dwyer, Mary A.; Chang, Ching Yi; McDonnell, Donald P.

In: Molecular Endocrinology, Vol. 23, No. 8, 01.08.2009, p. 1171-1182.

Research output: Contribution to journalArticle

Grasfeder, LL, Gaillard, S, Hammes, SR, Ilkayeva, O, Newgard, CB, Hochberg, RB, Dwyer, MA, Chang, CY & McDonnell, DP 2009, 'Fasting-induced hepatic production of DHEA is regulated by PGC-1α, ERRα, and HNF4α', Molecular Endocrinology, vol. 23, no. 8, pp. 1171-1182. https://doi.org/10.1210/me.2009-0024
Grasfeder, Linda L. ; Gaillard, Stephanie ; Hammes, Stephen R. ; Ilkayeva, Olga ; Newgard, Christopher B. ; Hochberg, Richard B. ; Dwyer, Mary A. ; Chang, Ching Yi ; McDonnell, Donald P. / Fasting-induced hepatic production of DHEA is regulated by PGC-1α, ERRα, and HNF4α. In: Molecular Endocrinology. 2009 ; Vol. 23, No. 8. pp. 1171-1182.
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