Failure of adrenal corticosterone production in POMC-deficient mice results from lack of integrated effects of POMC peptides on multiple factors

Jason Karpac, Katarzyna Czyzewska, Andras Kern, Richard S. Brush, Robert E. Anderson, Ute Hochgeschwender

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Production of corticosteroids from the adrenal gland is a multistep process in which corticosterone is enzymatically processed from its precursor cholesterol. The main hormone regulating the production of corticosterone is the proopiomelanocortin (POMC)-derived adrenocorticotropic hormone (ACTH). Adrenals of POMC-deficient (POMC-/-) mice do not produce corticosterone either at basal levels or in response to acute stimulation with ACTH. However, pharmacological amounts of ACTH delivered continuously elicit corticosterone production over time. To define the relative effects of ACTH on individual factors involved in corticosterone production, parameters of adrenal cholesterol metabolism and steroidogenesis were examined in POMC-/- mice compared with wildtype and ACTH-treated mutant mice. POMC-/- adrenals lack cholesterol esters (CE); adrenal CE is restored with ACTH treatment. However, discontinuation of ACTH treatment stops corticosterone production despite the presence of adrenal CE. Failure of corticosterone production by POMC-/- adrenals occurs despite the constitutive presence of transcripts of genes required for cholesterol metabolism and steroidogenesis. Levels of key proteins involved in selective cholesterol uptake and steroidogenesis were attenuated; ACTH treatment increased these protein levels, most significantly those of the receptor responsible for selective uptake of CE, scavenger receptor class B, type I (SR-BI). Our studies reveal that failure of corticosterone production of POMC-/- adrenal glands and its pharmacological reconstitution by ACTH are not mediated by any one individual protein, but rather as an integrated effect on multiple factors from import of the substrate cholesterol to its conversion to corticosterone.

Original languageEnglish
Pages (from-to)E446-E455
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume295
Issue number2
DOIs
StatePublished - Aug 2008

Keywords

  • Adrenocorticotropic hormone
  • Cholesterol
  • Gene expression
  • Proopiomelanocortin
  • Scavenger receptor class B, type I

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