Control of steroid 21-oic acid synthesis by peroxisome proliferator- activated receptor α and role of the hypothalamic-pituitary-adrenal axis

Ting Wang, Yatrik M. Shah, Tsutomu Matsubara, Yueying Zhen, Tomotaka Tanabe, Tomokazu Nagano, Serge Fotso, Kristopher W. Krausz, Mark Zabriskie, Jeffrey R. Idle, Frank J. Gonzalez

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

A previous study identified the peroxisome proliferator-activated receptor α (PPARα) activation biomarkers 21-steroid carboxylic acids 11β-hydroxy-3,20-dioxopregn-4-en-21-oic acid (HDOPA)and 11β,20-dihydroxy-3-oxo-pregn-4-en-21-oic acid (DHOPA). In the present study, the molecular mechanism and the metabolic pathway of their production were determined. The PPARα-specific time-dependent increases in HDOPA and 20α-DHOPA paralleled the development of adrenal cortex hyperplasia, hypercortisolism, and spleen atrophy, which was attenuated in adrenalectomized mice. Wy-14,643 activation of PPARα induced hepatic FGF21, which caused increased neuropeptide Y and agouti-related protein mRNAs in the hypothalamus, stimulation of the agouti-related protein/neuropeptide Y neurons, and activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increased adrenal cortex hyperplasia and corticosterone production, revealing a link between PPARα and the HPA axis in controlling energy homeostasis and immune regulation. Corticosterone was demonstrated as the precursor of 21-carboxylic acids both in vivo and in vitro. Under PPARα activation, the classic reductive metabolic pathway of corticosterone was suppressed, whereas an alternative oxidative pathway was uncovered that leads to the sequential oxidation on carbon 21 resulting in HDOPA. The latter was then reduced to the end product 20α-DHOPA.Hepatic cytochromes P450, aldehyde dehydrogenase (ALDH3A2), and 21-hydroxysteroid dehydrogenase (AKR1C18) were found to be involved in this pathway. Activation of PPARα resulted in the induction of Aldh3a2 and Akr1c18, both of which were confirmed as target genes through introduction of promoter luciferase reporter constructs into mouse livers in vivo. This study underscores the power of mass spectrometry-based metabolomics combined with genomic and physiologic analyses in identifying downstream metabolic biomarkers and the corresponding upstream molecular mechanisms.

Original languageEnglish (US)
Pages (from-to)7670-7685
Number of pages16
JournalJournal of Biological Chemistry
Volume285
Issue number10
DOIs
StatePublished - Mar 5 2010
Externally publishedYes

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Peroxisome Proliferator-Activated Receptors
Steroids
Chemical activation
Acids
Agouti-Related Protein
Corticosterone
Neuropeptide Y
Adrenal Cortex
Biomarkers
Carboxylic Acids
Metabolic Networks and Pathways
Hyperplasia
Liver
Aldehyde Dehydrogenase
Hydroxysteroid Dehydrogenases
Metabolomics
Cushing Syndrome
Luciferases
Cytochrome P-450 Enzyme System
Hypothalamus

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Control of steroid 21-oic acid synthesis by peroxisome proliferator- activated receptor α and role of the hypothalamic-pituitary-adrenal axis. / Wang, Ting; Shah, Yatrik M.; Matsubara, Tsutomu; Zhen, Yueying; Tanabe, Tomotaka; Nagano, Tomokazu; Fotso, Serge; Krausz, Kristopher W.; Zabriskie, Mark; Idle, Jeffrey R.; Gonzalez, Frank J.

In: Journal of Biological Chemistry, Vol. 285, No. 10, 05.03.2010, p. 7670-7685.

Research output: Contribution to journalArticle

Wang, T, Shah, YM, Matsubara, T, Zhen, Y, Tanabe, T, Nagano, T, Fotso, S, Krausz, KW, Zabriskie, M, Idle, JR & Gonzalez, FJ 2010, 'Control of steroid 21-oic acid synthesis by peroxisome proliferator- activated receptor α and role of the hypothalamic-pituitary-adrenal axis', Journal of Biological Chemistry, vol. 285, no. 10, pp. 7670-7685. https://doi.org/10.1074/jbc.M109.090175
Wang, Ting ; Shah, Yatrik M. ; Matsubara, Tsutomu ; Zhen, Yueying ; Tanabe, Tomotaka ; Nagano, Tomokazu ; Fotso, Serge ; Krausz, Kristopher W. ; Zabriskie, Mark ; Idle, Jeffrey R. ; Gonzalez, Frank J. / Control of steroid 21-oic acid synthesis by peroxisome proliferator- activated receptor α and role of the hypothalamic-pituitary-adrenal axis. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 10. pp. 7670-7685.
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AU - Zhen, Yueying

AU - Tanabe, Tomotaka

AU - Nagano, Tomokazu

AU - Fotso, Serge

AU - Krausz, Kristopher W.

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