title: Control of steroid 21-oic acid synthesis by peroxisome proliferator-activated receptor alpha and role of the hypothalamic-pituitary-adrenal axis.
abstract: A previous study identified the peroxisome proliferator-activated receptor alpha (PPARalpha) activation biomarkers 21-steroid carboxylic acids 11beta-hydroxy-3,20-dioxopregn-4-en-21-oic acid (HDOPA) and 11beta,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 PPARalpha-specific time-dependent increases in HDOPA and 20alpha-DHOPA paralleled the development of adrenal cortex hyperplasia, hypercortisolism, and spleen atrophy, which was attenuated in adrenalectomized mice. Wy-14,643 activation of PPARalpha 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 PPARalpha 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 PPARalpha 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 20alpha-DHOPA. Hepatic cytochromes P450, aldehyde dehydrogenase (ALDH3A2), and 21-hydroxysteroid dehydrogenase (AKR1C18) were found to be involved in this pathway. Activation of PPARalpha 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.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Matsubara
authors.forename: Yueying
authors.initials: Y
authors.lastname: Zhen
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Tanabe
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Nagano
authors.forename: Serge
authors.initials: S
authors.lastname: Fotso
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: T Mark
authors.initials: TM
authors.lastname: Zabriskie
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Idle
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000305:Adrenal Cortex Hormones / Q000378:metabolism; D000315:Adrenalectomy; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism*; D005215:Fasting; D006908:Hydroxyprogesterones / Q000737:chemistry / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D020025:Peroxisome Proliferators / Q000008:administration & dosage / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000502:physiology*; D011372:Progestins / Q000737:chemistry / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage / Q000378:metabolism; D014556:Urine / Q000737:chemistry
chemical_list: D000305:Adrenal Cortex Hormones; D015415:Biomarkers; D006908:Hydroxyprogesterones; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011372:Progestins; D011743:Pyrimidines; C006253:pirinixic acid; D000429:Alcohol Oxidoreductases; D000445:Aldehyde Oxidoreductases; C038828:long-chain-aldehyde dehydrogenase