On the Mechanism of Action of ACTH

Garren, Leonard D.; Gill, Gordon N.; Masui, Hideo; Walton, Gordon M.

doi:10.1016/b978-0-12-571127-2.50035-3

Cited by 137 publications

(91 citation statements)

References 58 publications

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“…The tropic hormones, ACTH and gonadotropins (LH, FSH) acutely stimulate this process by facilitating the availability of cytosolic free cholesterol and its transport to and accumulation in the inner mitochondrial CYP11A1 sites. When steroidogenic cells are stimu-lated with tropic hormones in the presence of protein synthesis inhibitors such as cycloheximide, cholesterol accumulates in the outer mitochondrial membrane and is not transferred to the inner mitochondrial membrane [54][55][56][57]. Therefore, it has been proposed that a labile protein is required for cholesterol delivery to the inner mitochondrial membrane microdomains containing CYP11A1 [26,53,59].…”

Section: Hormonal Regulation Of Steroidogenesismentioning

confidence: 99%

“…In the first step, the tropic hormonemediated increased cAMP formation (second messenger) stimulates PKA [54,60], leading to phosphorylation (activation) of a cholesteryl esterase, which, in turn, hydrolyzes stored cholesteryl esters (in the form of lipid droplets) and generates increased concentrations of free cholesterol, the substrate for CYP11A1 [26,35]. Subsequently, the mobilized cholesterol is transported to the outer mitochondrial membrane.…”

Section: Hormonal Regulation Of Steroidogenesismentioning

confidence: 99%

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Impact of Aging on Steroid Hormone Biosynthesis and Secretion

Zaidi¹

2013

TOLSJ

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Steroid hormones are lipophilic, low-molecular weight organic compounds all of which are derived from cholesterol. They are primarily synthesized by steroidogenic glands such as gonads (ovary and testis), the adrenal gland and, during pregnancy, by the placental trophoblasts. Limited steroid synthesis also takes place in the brain. Steroid hormones are crucial for the proper functioning of the body. They mediate a wide variety of vital physiological functions, ranging from maintaining normal reproductive function and secondary sexual characteristics, to regulating virtually every metabolic process in the body. Like many age-related endocrine disorders, aging also progressively impacts the tissue-specific synthesis and secretion of steroid hormones. The goal of this review is to summarize the effects of aging on steroid hormone synthesis and secretion by the adrenal gland and gonads of both human and experimental animal models, to describe the potential involvement of excessive oxidative stress in mediating age-related alterations in steroidogenesis, and to discuss the possible underlying mechanisms involved.

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Section: Hormonal Regulation Of Steroidogenesismentioning

confidence: 99%

Section: Hormonal Regulation Of Steroidogenesismentioning

confidence: 99%

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

Zaidi¹

2013

TOLSJ

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“…The rate-limiting step in steroidogenesis is the conversion of cholesterol into pregnenolone, a side-chain cleavage reaction that takes place in the mitochondrial inner membrane catalyzed by cytochrome P450scc and its associated electrontransport chain (1). In the adrenal cortex and gonads, the translocation of cholesterol substrate to P450scc is under the control of corticotropin (ACTH) and luteinizing hormone (LH), respectively, through the intermediacy of the steroidogenic acute regulatory protein (StAR) (2).…”

mentioning

confidence: 99%

MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis

Watari¹,

Arakane²,

Moog-Lutz³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

223

154

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MLN64 is a protein that is highly expressed in certain breast carcinomas. The C terminus of MLN64 shares significant homology with the steroidogenic acute regulatory protein (StAR), which plays a key role in steroid hormone biosynthesis by enhancing the intramitochondrial translocation of cholesterol to the cholesterol side-chain cleavage enzyme. We tested the ability of MLN64 to stimulate steroidogenesis by using COS-1 cells cotransfected with plasmids expressing the human cholesterol side-chain cleavage enzyme system and wild-type and mutant MLN64 proteins. Wild-type MLN64 increased pregnenolone secretion in this system 2-fold. The steroidogenic activity of MLN64 was found to reside in the C terminus of the protein, because constructs from which the C-terminal StAR homology domain was deleted had no steroidogenic activity. In contrast, removal of N-terminal sequences increased MLN64's steroidogenesisenhancing activity. MLN64 mRNA was found in many human tissues, including the placenta and brain, which synthesize steroid hormones but do not express StAR. Western blot analysis revealed the presence of lower molecular weight immunoreactive MLN64 species that contain the C-terminal sequences in human tissues. Homologs of both MLN64 and StAR were identified in Caenorhabditis elegans, indicating that the two proteins are ancient. Mutations that inactivate StAR were correlated with amino acid residues that are identical or similar among StAR and MLN64, indicating that conserved motifs are important for steroidogenic activity. We conclude that MLN64 stimulates steroidogenesis by virtue of its homology to StAR.

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“…Phosphatidylcholine did not affect alkaline CEase activity in any of the tissues, as shown in Fig. 4 [5][6][7], and adrenal CEase activity can be significantly enhanced by ACTH [8,11]. The nature and regulation of adrenal CEase had been well studied in rats [8], cattle [12], and guinea pigs [9], while those of CEase in human adrenals were still obscure.…”

Section: Effect Of Phosphatidylcholinementioning

confidence: 99%

“…-4]. It is well known that free cholesterol for adrenal steroidogenesis is mainly provided by hydrolysis of the deposited cholesterol esters by cholesterol esterase (CEase) [5][6][7][8]. Adrenal CEase is an important enzyme, which can convert cholesterol esters into free cholesterol, thus providing it as a substrate for the cholesterol sidechain cleavage enzyme complex which is known to be the rate-limiting step for adrenal steroidogenesis.…”

mentioning

confidence: 99%

Regulation of Cholesterol Metabolism in Adrenal Cortex: Comparative Studies on Cholesterol Esterase in Human Adrenal Glands.

Nishikawa

Mikami²,

Yoshida³

et al. 1993

Endocr J

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Abstract. We have studied the nature and characteristics of cholesterol esterase (CEase) in human adrenal adenoma and hyperplasia tissues showing Cushing's syndrome, comparing with those in normal tissue. Each tissue demonstrated that two pH optima were found at around 4.5 and 8.0. The results of a subcellular distribution study show that acid and alkaline CEase are mainly located in lysosomes and microsomes, respectively. Our previous data suggested that phosphatidylcholine which was sonicated with cholesteryl oleate as a substrate may play a crucial role in the regulation of CEase in rat adrenal. The effect of phosphatidylcholine was therefore investigated in the present study. Acid CEase in normal tissue was increased in a dose-dependent manner by phosphatidylcholine, but not in the adenoma or hyperplasia tissues. None of those tissues showed any enhancement in alkaline CEase activity when phosphatidylcholine was added to the substrates. It is therefore suggested that the mechanism of regulation of CEase among three different kinds of human adrenals may be different from the data for the effect of phosphatidylcholine.Basal activity of acid CEase in adenoma and hyperplasia was significantly higher than that in normal tissue, and also that of alkaline CEase in hyperplasia tissue was significantly higher than that in normal tissue. Thus it is suggested that such an adrenocortical disorder as Cushing's syndrome due to adenoma and diffuse hyperplasia of the adrenal cortex may posscss the nature and characteristics of autonomy of steroidogenesis which seems to be induced by the active metabolism of cholesterol, when compared with normal tissue.

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On the Mechanism of Action of ACTH

Cited by 137 publications

References 58 publications

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis

Regulation of Cholesterol Metabolism in Adrenal Cortex: Comparative Studies on Cholesterol Esterase in Human Adrenal Glands.

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