ACTH control of cholesterol side-chain cleavage at adrenal mitochondrial cytochrome P-450scc. Regulation of intramitochondrial cholesterol transfer

Privalle, Christopher T.; McNamara, Brian C.; Dhariwal, Mohan S; Jefcoate, Colin R.

doi:10.1016/0303-7207(87)90195-x

Cited by 67 publications

(24 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies [12, 131 which quantified the cholesterol content of separated adrenal mitochondrial inner and outer membranes from cycloheximidelcorticotropin-treated rats have demonstrated the accumulation of cholesterol in an outer-membrane fraction. However, Privalle et al [13] found that under some conditions not all of the accumulated sterol could be accounted for by the sum of that in the inner and outer membranes, and proposed that there is a pool of cholesterol loosely bound to mitochondria. Despite the finding that cholesterol can accumulate in mitochondria in cycloheximide-treated cells, evidence for its ability to serve as a steroidogenic precursor is inconclusive.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol trafficking in steroidogenic cells

Stevens

Lambeth

1993

European Journal of Biochemistry

View full text Add to dashboard Cite

Peptide hormones activate steroid hormone biosynthesis in responsive tissues by stimulating the delivery of cholesterol to a steroidogenic pool, thought to be located in the inner mitochondrial membrane. At this site, it is metabolized to pregnenolone, the precursor of the steroid hormones, by side-chain-cleaving cytochrome P-450 (cytochrome P-45Oscc). In the presence of aminoglutethimide (an inhibitor of cytochrome P-45Oscc) and an activating stimulus, cholesterol accumulates in the steroidogenic pool, and increased pregnenolone generation is observed upon removal of the inhibitor. Using Y-1 adrenocortical cells and MA-I0 Leydig tumor cells, we now provide evidence for a distinct, functionally relevant cholesterol pool which precedes the steroidogenic pool, which we designate the pre-steroidogenic pool. This pool was defined by activating the cells with 8-bromo-adenosine 3',5'-cyclic monophosphoric acid in the presence of cycloheximide, an inhibitor of steriodogenesis. Following a wash procedure, which removed 8-bromo-adenosine 3',5'-cyclic monophosphoric acid and cycloheximide, augmented pregnenolone synthesis was observed. Unlike synthesis from the steroidogenic pool, pregnenolone formation from pre-steroidogenic pool in Y-1 cells indicates that this pool is somewhat smaller than the steroidogenic pool. The results support a cholesterol-trafficking model in which cycloheximide-sensitive transport from the pre-steroidogenic pool to the steroidogenic pool precedes metabolism, and is regulated by CAMP.Steroidogenic cells respond in a tissue-specific manner to peptide hormones by synthesizing unique steroid hormones. Adrenal cortex cells are activated by the pituitary hormone corticotropin to generate cortisol (or corticosterone in the rat), while Leydig cells respond to luteinizing hormone by synthesizing testosterone. Although the activators and end products differ, the signal-transduction pathway(s) appears to be the same. Binding of the hormone to its GTP-bindingprotein-linked receptor activates adenylate cyclase to generate CAMP [l, 21. This second messenger may act through a CAMP-dependent protein kinase to affect several metabolic processes. Free cholesterol is liberated from intracellular stores of cholesterol ester by the phosphorylation-dependent activation of cholesterol-ester hydrolase [3, 41. This cholesterol, as well as other free cholesterol, is thought to be transported to a pool where it is available for metabolism by a side-chain-cleavage reaction to form pregnenolone [5]. This reaction is catalyzed by the inner-mitochondrial-membranelocalized enzyme [6] side-chain-cleaving (SCC) cytochrome P-450 (cytochrome P-45Oscc ; systematic name cytochrome Although the rate-limiting step in steroid hormone biosynthesis is cholesterol side-chain cleavage, recent evidence P-45011 A1 [7]).

show abstract

Section: Discussionmentioning

confidence: 99%

Cholesterol trafficking in steroidogenic cells

Stevens

Lambeth

1993

European Journal of Biochemistry

View full text Add to dashboard Cite

show abstract

“…Early studies in adrenocortical cells have demonstrated that the inhibitor of protein translation, cycloheximide, prevents the increase in the rate of steroid synthesis induced by ACTH (10,11). The cycloheximide-sensitive step in steroidogenesis has been located to the ACTH-activated cholesterol transport to the inner mitochondrial membrane (10).…”

Section: Discussionmentioning

confidence: 99%

“…While the transport of cholesterol from lipid droplets to the outer mitochondrial membrane was found not to be affected by inhibitors of protein synthesis in ACTH-stimulated adrenal cells, by contrast, the subsequent delivery of cholesterol to the inner mitochondrial membrane has been shown to be blocked by cycloheximide, with a concomitant inhibition of steroid synthesis (10,11). As a consequence, newly synthesized "labile" proteins, among others, have been proposed to be significant mediators of the acute steroidogenic response.…”

Section: ؉mentioning

confidence: 99%

Submitochondrial Distribution of Three Key Steroidogenic Proteins (Steroidogenic Acute Regulatory Protein and Cytochrome P450scc and 3β-Hydroxysteroid Dehydrogenase Isomerase Enzymes) upon Stimulation by Intracellular Calcium in Adrenal Glomerulosa Cells

Cherradi

Rossier

Vallotton

et al. 1997

Journal of Biological Chemistry

170

View full text Add to dashboard Cite

In adrenal glomerulosa cells, angiotensin II (Ang II) and potassium stimulate aldosterone synthesis through activation of the calcium messenger system. The ratelimiting step in steroidogenesis is the transfer of cholesterol to the inner mitochondrial membrane. This transfer is believed to depend upon the presence of the steroidogenic acute regulatory (StAR) protein. (Ang II) 1 and K ϩ act as regulators of aldosterone synthesis and secretion in adrenal glomerulosa cells. The crucial role of the Ca 2ϩ messenger in the acute regulation of aldosterone production is firmly established (1-5). Indeed, the steroidogenic response of isolated adrenal cells to Ang II and K ϩ is highly dependent upon extracellular Ca 2ϩ concentration (6) and can be blocked by inhibitors of Ca 2ϩ influx across the plasma membrane (4). Moreover, calmodulin antagonists have been shown to inhibit Ang IIstimulated aldosterone production in zona glomerulosa cells (7).Traditionally, aldosterone biosynthesis is functionally divided into three consecutive phases. (i) In the early mitochondrial steps, cholesterol is transported from intracellular lipid droplets into the outer mitochondrial membrane (OM) and then to the inner mitochondrial membrane (IM). The latter step represents the rate-limiting process in all steroidogenic pathways (8) and is followed by the conversion of cholesterol to pregnenolone by the cytochrome P450 scc enzyme. (ii) The intermediate steps take place on the endoplasmic reticulum and involve the conversion of pregnenolone to progesterone by 3␤-hydroxysteroid dehydrogenase isomerase and then to 11-deoxycorticosterone. (iii) The late steroidogenic steps are localized back in the mitochondria and include the formation of corticosterone and its conversion to aldosterone by cytochrome P450 11␤ .The regulation of intramitochondrial cholesterol transfer by cAMP-dependent mechanisms has been extensively studied (9). While the transport of cholesterol from lipid droplets to the outer mitochondrial membrane was found not to be affected by inhibitors of protein synthesis in ACTH-stimulated adrenal

show abstract

“…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

View full text Add to dashboard Cite

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...

show abstract

ACTH control of cholesterol side-chain cleavage at adrenal mitochondrial cytochrome P-450scc. Regulation of intramitochondrial cholesterol transfer

Cited by 67 publications

References 37 publications

Cholesterol trafficking in steroidogenic cells

Cholesterol trafficking in steroidogenic cells

Submitochondrial Distribution of Three Key Steroidogenic Proteins (Steroidogenic Acute Regulatory Protein and Cytochrome P450scc and 3β-Hydroxysteroid Dehydrogenase Isomerase Enzymes) upon Stimulation by Intracellular Calcium in Adrenal Glomerulosa Cells

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

Contact Info

Product

Resources

About