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This Article Full Text Full Text (PDF) All Versions of this Article: 295/2/E446    most recent 00762.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Karpac, J. Articles by Hochgeschwender, U. Search for Related Content PubMed PubMed Citation Articles by Karpac, J. Articles by Hochgeschwender, U.

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

¹Molecular, Cell and Developmental Biology Program, Oklahoma Medical Research Foundation; and ²Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Submitted 6 December 2007 ; accepted in final form 10 June 2008

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 wild-type 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.

proopiomelanocortin; adrenocorticotropic hormone; cholesterol; scavenger receptor class B, type I; gene expression