A Study of the Mechanisms by Which Adrenocorticotropic Hormone Maintains Adrenal Steroidogenic Responsiveness*

Ney, Robert L.; Dexter, R. N.; Davis, Warren W.; Garren, Leonard D.

doi:10.1172/jci105681

Cited by 31 publications

(11 citation statements)

References 16 publications

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“…In the absence of ACTH free adrenal cholesterol presumably returns to plasma in an unmetabolized form whereas under the influence of ACTH a major fraction (see below) is first diverted towards the pathways of steroid hormone synthesis. This concept is compatible with the known mode of action of ACTH which accelerates the conversion of adrenal cholesterol into A5-pregnenolone and of A5-pregnenolone into steroid hormones (11,44). It also confirms and explains the experimental observations by Sayers, Sayers, Frey, White, and Long (40) who showed that hypophysectomized rats are still capable of replenishing depleted stores of adrenal cholesterol.…”

Section: Parameters Of Adrenal Cholesterol In Control Studiessupporting

confidence: 87%

Metabolism of adrenal cholesterol in man

Borkowski¹,

Delcroix²,

Levin³

1972

J. Clin. Invest.

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A B S T R A C T The kinetics of plasma and adrenal cholesteral equilibration were analyzed in patients undergoing bilateral adrenalectomy for generalized mammary carcinoma. A biological model is proposed to help in the understanding of adrenal cholesterol physiology. It comprises two intracellular compartments: (1) A compartment of free adrenal cholesterol which is small (of the order of 17 mg) but turns over very fast; it is renewed approximately 8 times per day: 3 times by the inflow of free plasma cholesterol, and 5 times by the hydrolysis of esterified adrenal cholesterol, the contribution of adrenal cholesterol synthesis appearing to be relatively small. (2) A compartment of esterified adrenal cholesterol which is 20 times larger; it is constantly renewed by in situ esterification and hydrolysis with a daily fractional turnover rate of the order of 0.25. The direct and selective accumulation of plasma cholesteryl esters is practically absent. Only free adrenal cholesterol returns to plasma, mostly after conversion into steroid "hormones."However small the synthesis of adrenal cholesterol may be, it seems more important in the zona "reticularis." On the other hand, the inflow of plasma cholesterol and the turnover of the free adrenal compartment tend to be faster in the zona "fasciculata." The equilibration of plasma and adrenal cholesterol can proceed unmodified under conditions of ACTH suppression.

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Section: Parameters Of Adrenal Cholesterol In Control Studiessupporting

confidence: 87%

Metabolism of adrenal cholesterol in man

Borkowski¹,

Delcroix²,

Levin³

1972

J. Clin. Invest.

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“…nous A5-pregnenolone, progesterone, or deoxycorticosterone, the formation of corticosterone is increased (20). To test whether the adrenocortical carcinoma could also perform this series of reactions, tumor tissue was incubated with exogenous A5-pregnenolone or progesterone, and it was found that corticosterone production was enhanced (Table IV).…”

Section: Resultsmentioning

confidence: 99%

Abnormal regulation of adenosine 3′,5′-monophosphate and corticosterone formation in an adrenocortical carcinoma

Ney¹,

Hochella²,

Grahame-Smith³

et al. 1969

J. Clin. Invest.

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A B S T R A C T A spontaneously occurring rat adrenocortical carcinoma which produces corticosterone was maintained by transplantation. The In normal adrenals, ACTH increases the activity of adenyl cyclase which catalyzes the conversion of adenosine triphosphate (ATP) to adenosine-3',5'-monophosphate (cyclic AMP), the latter then serving as an intracellular regulator of steroidogenesis. ACTH failed to increase cyclic AMP levels in the tumor in vivo or in slices in vitro, conditions under which there were 50-and 20-fold increases in nontumorous adrenals. However, in homogenates fortified with exogenous ATP, adenyl cyclase activity was comparable in the tumor and adrenals, and cyclic AMP formation was increased 3-fold by ACTH in each. As measured in homogenates, the tumor did not possess a greater ability to destroy cyclic AMP than did normal adrenals. Although ATP levels in the carcinoma were found to be considerably lower than those in normal adrenals, it was not clear that this finding can explain the inability of ACTH to increase cyclic AMP levels in intact tumor cells.While the failure to normally influence cyclic AMP levels in the carcinoma cells could be an important factor in the lack of a steroid response to ACTH, several lines of evidence suggest that the tumor possesses one or more additional abnormalities in the regulation of steroidogenesis. First, in the absence of ACTH stimulaDr. Butcher is an Investigator, Howard Hughes Medical Institute.

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“…It is positioned centrally within the hypothalamic-pituitary-adrenal (HPA) axis: stress leads to release of corticotropin-releasing factor (CRF) from the hypothalamus, which in turn stimulates corticotroph cells of the anterior pituitary to release ACTH, which stimulates the adrenal to produce corticosterone. Production of corticosterone then negatively regulates the release of CRF in a feedback loop to the hypothalamus.At the molecular level, ACTH has been shown to regulate many, if not all, of the factors involved in adrenal corticosteroidogenesis, among them the receptors which mediate uptake of cholesterol into the cell, the enzymes which mediate conversion of cholesterol esters to free cholesterol and translocation into mitochondria, as well as the mitochondrial enzymes converting cholesterol to corticosterone (7,8,17,18,33). Regulation of these factors was assessed at the gene or protein level either by adding ACTH to in vitro systems such as primary cell cultures from human, bovine, rat, and mouse adrenals, as well as the Y1 tumor adrenal cell line (10,23,27,28,30,31), or by removing ACTH in vivo through hypophysectomy of rats (16,18,29).…”

mentioning

confidence: 99%

“…Regulation of these factors was assessed at the gene or protein level either by adding ACTH to in vitro systems such as primary cell cultures from human, bovine, rat, and mouse adrenals, as well as the Y1 tumor adrenal cell line (10,23,27,28,30,31), or by removing ACTH in vivo through hypophysectomy of rats (16,18,29). The resulting effects demonstrate either the potential of ACTH to regulate a particular factor (in vitro experiments) or the reaction of intact adrenals to the sudden depletion of ACTH (in vivo experiments).…”

mentioning

confidence: 99%

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

Karpac

Czyzewska²,

Kern³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Karpac J, Czyzewska K, Kern A, Brush RS, Anderson RE, Hochgeschwender U. Failure of adrenal corticosterone production in POMC-deficient mice results from lack of integrated effects of POMC peptides on multiple factors. Am J Physiol Endocrinol Metab 295: E446 -E455, 2008. First published June 17, 2008 doi:10.1152/ajpendo.00762.2007.-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 Ϫ/Ϫ ) 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 Ϫ/Ϫ mice compared with wildtype and ACTH-treated mutant mice. POMC Ϫ/Ϫ 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 Ϫ/Ϫ 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 Ϫ/Ϫ 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 SYNTHESIS OF CORTICOSTEROIDS in the adrenal gland requires cholesterol as the precursor, which is then metabolized in the steroidogenic pathway. Numerous steps, from the import of cholesterol from plasma into adrenal cells, the conversion of cholesterol esters to free cholesterol, movement of free cholesterol into the inner mitochondrial membrane, to the enzymatic conversion in the mitochondria of cholesterol to pregnenolone, progesterone, deoxycorticosterone, and, finally, corticosterone have to function to produce baseline levels of corticosterone. Importantly, they need to be highly regulatable in order to respond to acute stress with high output of corticosterone.Adrenocorticotropic hormone (ACTH), a 39-amino acid peptide processed in the pituitary from the proopiomelanocortin (POMC) prohormone, is the key mediator of adrenal cor...

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A Study of the Mechanisms by Which Adrenocorticotropic Hormone Maintains Adrenal Steroidogenic Responsiveness*

Cited by 31 publications

References 16 publications

Metabolism of adrenal cholesterol in man

Metabolism of adrenal cholesterol in man

Abnormal regulation of adenosine 3′,5′-monophosphate and corticosterone formation in an adrenocortical carcinoma

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

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