Steroid Chemistry and Steroid Hormone Action (original) (raw)
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Cholesterol ester droplets and steroidogenesis
Molecular and Cellular Endocrinology, 2013
Intracellular lipid droplets (LDs) are dynamic organelles that contain a number of associated proteins including perilipin (Plin) and vimentin. Cholesteryl ester (CE)-rich LDs normally accumulate in steroidogenic cells and their mobilization is the preferred initial source of cholesterol for steroidogenesis. Plin1a, 1b and 5 were found to preferentially associate with triacylglycerol-rich LDs and Plin1c and 4 to associate with CE-rich LDs, but the biological significance of this remains unanswered. Vimentin null mice were found to have decreased ACTH-stimulated corticosterone levels, and decreased progesterone levels in females, but normal hCG-stimulated testosterone levels in males. Smaller LDs were seen in null cells. Lipoprotein cholesterol delivery to adrenals and ovary was normal, as was the expression of steroidogenic genes; however, the movement of cholesterol to mitochondria was reduced in vimentin null mice. These results suggest that vimentin is important in the maintenance of CE-rich LDs and in the movement of cholesterol for steroidogenesis.
Nutrition & Metabolism, 2010
Steroid hormones regulate diverse physiological functions such as reproduction, blood salt balance, maintenance of secondary sexual characteristics, response to stress, neuronal function and various metabolic processes. They are synthesized from cholesterol mainly in the adrenal gland and gonads in response to tissue-specific tropic hormones. These steroidogenic tissues are unique in that they require cholesterol not only for membrane biogenesis, maintenance of membrane fluidity and cell signaling, but also as the starting material for the biosynthesis of steroid hormones. It is not surprising, then, that cells of steroidogenic tissues have evolved with multiple pathways to assure the constant supply of cholesterol needed to maintain optimum steroid synthesis. The cholesterol utilized for steroidogenesis is derived from a combination of sources: 1) de novo synthesis in the endoplasmic reticulum (ER); 2) the mobilization of cholesteryl esters (CEs) stored in lipid droplets through cholesteryl ester hydrolase; 3) plasma lipoprotein-derived CEs obtained by either LDL receptor-mediated endocytic and/or SR-BI-mediated selective uptake; and 4) in some cultured cell systems from plasma membrane-associated free cholesterol. Here, we focus on recent insights into the molecules and cellular processes that mediate the uptake of plasma lipoprotein-derived cholesterol, events connected with the intracellular cholesterol processing and the role of crucial proteins that mediate cholesterol transport to mitochondria for its utilization for steroid hormone production. In particular, we discuss the structure and function of SR-BI, the importance of the selective cholesterol transport pathway in providing cholesterol substrate for steroid biosynthesis and the role of two key proteins, StAR and PBR/TSO in facilitating cholesterol delivery to inner mitochondrial membrane sites, where P450scc (CYP11A) is localized and where the conversion of cholesterol to pregnenolone (the common steroid precursor) takes place.
The LDL receptor is not necessary for acute adrenal steroidogenesis in mouse adrenocortical cells
AJP: Endocrinology and Metabolism, 2006
Steroid hormones are synthesized using cholesterol as precursor. To determine the functional importance of the LDL receptor and HSL in adrenal steroidogenesis, adrenal cells were isolated from control, HSL-/-, LDLR-/-, and double LDLR/HSL-/mice. The endocytic and selective uptake of human HDL 3 -derived cholesteryl esters did not differ among the mice, with selective uptake accounting for >97% of uptake. In contrast, endocytic uptake of either human LDL-or rat HDL-derived cholesteryl esters was reduced 80-85% in LDLR-/-and double LDLR/HSL-/-mice. There were no differences in the selective uptake of either human LDL-or rat HDL-derived cholesteryl esters among the mice. Maximum corticosterone production induced by ACTH or Bt 2 cAMP and lipoproteins was not altered in LDLR-/-mice, but was reduced 80-90% in HSL-/-mice. Maximum corticosterone production was identical in HSL-/-and double LDLR/HSL-/-mice. These findings suggest that, although the LDL receptor is responsible for endocytic delivery of cholesteryl esters from LDL and rat HDL to mouse adrenal cells, it appears to play a negligible role in the delivery of cholesterol for acute adrenal steroidogenesis in the mouse. In contrast, HSL occupies a vital role in adrenal steroidogenesis because of its link to utilization of selectively delivered cholesteryl esters from lipoproteins.
Towards a new model for the mechanism of action of steroids
Journal of Steroid Biochemistry, 1982
The classical model for the mechanism of action of steroids holds that unbound receptors for steroids reside exclusively in the cytoplasmic compartment and that they undergo translocation to the nucleus when bound to steroids in a process which is temperature sensitive. In the present study we looked at the localization of the estradiol receptor using autoradiography and biochemical procedures.
Steroids: genomic and non-genomic actions (Atena Editora)
Steroids: genomic and non-genomic actions (Atena Editora), 2023
Steroid hormones are important maintainers of human body homeostasis, in addition to having important roles in the development and maturation of fetal organs and controlling male and female reproductive cycles. Human steroids are produced from a common precursor, cholesterol, in specialized endocrine cells such as the testes, ovaries, and adrenal glands. Testosterone, estrogen, cortisol and aldosterone are some examples of the best-known steroid hormones. The common mechanism of action of steroids is genomic, which occurs through the binding of these hormones with intracellular receptors, which are ligand-dependent transcription factors, affecting the cell's gene transcription. However, some rapid physiological effects cannot be explained by the traditional model of action, as changes in the gene transcription process take a certain time to take effect. Thus, the non-genomic effects of steroids are currently being studied, which include actions on the cell membrane, where they alter the opening of ion channels and their cardiovascular effects. The article in question also addresses the two-step action model of steroid hormones, focusing on reproductive hormones and vitamin D.
Hennebert 2009 The-Journal-of-Steroid-Biochemistry-and-Molecular-Biology
2013
Cytochrome P4507B1 7␣-hydroxylates dehydroepiandrosterone (DHEA), epiandrosterone (EpiA) and 5␣androstane-3,17-diol (Adiol). 11-Hydroxysteroid dehydrogenase type 1 (11-HSD1) interconverts 7␣-and 7-forms. Whether the interconversion proceeds through oxido-reductive steps or epimerase activity was investigated. Experiments using [ 3 H]-labelled 7-hydroxy-DHEA, 7-hydroxy-EpiA and 7hydroxy-Adiol showed the 3 H-label to accumulate in the 7-oxo-DHEA trap but not in 7-oxo-EpiA or 7-oxo-Adiol traps. Computed models of 7-oxygenated steroids docked in the active site of 11-HSD1 either in a flipped or turned form relative to cortisone and cortisol. 7-Oxo-steroid reduction in 7␣-o r 7-hydroxylated derivatives resulted from either turned or flipped forms. 11-HSD1 incubation in H 2 18 O medium with each 7-hydroxysteroid did not incorporate 18 O in 7-hydroxylated derivatives of EpiA and Adiol independently of the cofactor used. Thus oxido-reductive steps apply for the interconversion of 7␣and 7-hydroxy-DHEA through 7-oxo-DHEA. Epimerization may proceed on the 7-hydroxylated derivatives of EpiA and Adiol through a mechanism involving the cofactor and Ser 170 . The physiopathological importance of this epimerization process is related to 7-hydroxy-EpiA production and its effects in triggering the resolution of inflammation.
Current Knowledge on the Acute Regulation of Steroidogenesis
Biology of reproduction, 2018
How rapid induction of steroid hormone biosynthesis occurs in response to trophic hormone stimulation of steroidogenic cells has been a subject of intensive investigation for approximately six decades. A key observation made very early was that acute regulation of steroid biosynthesis required swift and timely synthesis of a new protein whose role appeared to be involved in the delivery of the substrate for all steroid hormones, cholesterol, from the outer to the inner mitochondrial membrane where the process of steroidogenesis begins. It was quickly learned that this transfer of cholesterol to the inner mitochondrial membrane was the regulated and rate limiting step in steroidogenesis. Following this observation, the quest for this putative regulator protein(s) began in earnest in the late 1950s. This review provides a history of this quest, the candidate proteins that arose over the years, and facts surrounding their rise or decline. Only two have persisted-Translocator Protein (T...
2009
The transfer of cholesterol from the outer to the inner mitochondrial membrane is the rate-limiting step in hormone-induced steroid formation. To ensure that this step is achieved efficiently, free cholesterol must accumulate in excess at the outer mitochondrial membrane and then be transferred to the inner membrane. This is accomplished through a series of steps that involve various intracellular organelles, including lysosomes and lipid droplets, and proteins such as the translocator protein (18 kDa, TSPO) and steroidogenic acute regulatory (StAR) proteins. TSPO, previously known as the peripheral-type benzodiazepine receptor, is a high-affinity drug-and cholesterol-binding mitochondrial protein. StAR is a hormone-induced mitochondria-targeted protein that has been shown to initiate cholesterol transfer into mitochondria. Through the assistance of proteins such as the cAMP-dependent protein kinase regulatory subunit Iα (PKA-RIα) and the PKA-RIα-and TSPO-associated acyl-coenzyme A binding domain containing 3 (ACBD3) protein, PAP7, cholesterol is transferred to and docked at the outer mitochondrial membrane. The TSPO-dependent import of StAR into mitochondria, and the association of TSPO with the outer/inner mitochondrial membrane contact sites, drives the intramitochondrial cholesterol transfer and subsequent steroid formation. The focus of this review is on (i) the intracellular pathways and protein-protein interactions involved in cholesterol transport and steroid biosynthesis and (ii) the roles and interactions of these proteins in endocrine pathologies and neurological diseases where steroid synthesis plays a critical role. j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b b a l i p