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Fasting-Induced Hepatic Production of DHEA Is Regulated by PGC-1, ERR, and HNF4

Department of Pharmacology and Cancer Biology (L.L.G., S.G., C.B.N., M.A.D., C.C., D.P.M.) and Sarah W. Stedman Nutrition and Metabolism Center (O.I., C.B.N.), Duke University Medical Center, Durham, North Carolina 27710; Division of Endocrinology and Metabolism (S.R.H.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Obstetrics, Gynecology, and Reproductive Sciences (R.B.H.), Yale University School of Medicine, New Haven, Connecticut 06510

Address all correspondence and requests for reprints to: Dr. Donald McDonnell, Duke University Medical Center, Pharmacology and Cancer Biology, Box 3813, Durham, North Carolina 27710. E-mail: donald.mcdonnell{at}duke.edu.

The transcriptional coactivator peroxisome proliferator-activated receptor- coactivator (PGC)-1 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-1 regulation 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)- mediates PGC-1’s induction of CYP11A1 and binds within the first intron of the CYP11A1 gene. Both ERR- and hepatocyte nuclear factor-4 are required for PGC-1-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-1 and 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   HNF4α  |  ERRα

Coregulators:   PGC-1