Karpac Jason, Czyzewska Katarzyna, Kern Andras, Brush Richard S, Anderson Robert E, Hochgeschwender Ute
Department of Neurobiology, Duke University Medical Center, 421 Research Drive, Durham, NC 27710, USA.
Am J Physiol Endocrinol Metab. 2008 Aug;295(2):E446-55. doi: 10.1152/ajpendo.00762.2007. Epub 2008 Jun 17.
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.
肾上腺皮质类固醇的产生是一个多步骤过程，在此过程中，皮质酮由其前体胆固醇经酶促加工而成。调节皮质酮产生的主要激素是源自阿黑皮素原（POMC）的促肾上腺皮质激素（ACTH）。POMC缺陷（POMC(-/-)）小鼠的肾上腺在基础水平或对ACTH急性刺激的反应中均不产生皮质酮。然而，持续给予药理剂量的ACTH会随着时间的推移引发皮质酮的产生。为了确定ACTH对参与皮质酮产生的各个因素的相对影响，与野生型和ACTH处理的突变小鼠相比，在POMC(-/-)小鼠中检测了肾上腺胆固醇代谢和类固醇生成的参数。POMC(-/-)肾上腺缺乏胆固醇酯（CE）；ACTH治疗可使肾上腺CE恢复。然而，尽管存在肾上腺CE，但停止ACTH治疗会停止皮质酮的产生。尽管存在胆固醇代谢和类固醇生成所需基因的转录本，但POMC(-/-)肾上腺仍无法产生皮质酮。参与选择性胆固醇摄取和类固醇生成的关键蛋白水平降低；ACTH治疗可提高这些蛋白水平，最显著的是负责选择性摄取CE的受体，即B类I型清道夫受体（SR-BI）的蛋白水平。我们的研究表明，POMC(-/-)肾上腺皮质酮产生失败及其通过ACTH进行的药理重建不是由任何一种单独的蛋白质介导的，而是对从底物胆固醇的导入到其转化为皮质酮的多个因素的综合作用。
