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Steroid biosynthesis

About: Steroid biosynthesis is a research topic. Over the lifetime, 1721 publications have been published within this topic receiving 58977 citations.


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Journal ArticleDOI
TL;DR: Results show that TAT-CRAC binds cholesterol and competes for cholesterol interaction with endogenous PBR, suggesting that the cytosolic carboxyl-terminal domain of PBR is responsible for taking up and bringing steroidogenic cholesterol into the mitochondria.
Abstract: We previously defined a cholesterol recognition/interaction amino acid consensus (CRAC; ATVLNYYVWRDNS) in the carboxyl terminus of the peripheral-type benzodiazepine receptor (PBR), an outer mitochondrial membrane protein involved in the regulation of cholesterol transport into the mitochondria, the rate-determining step in steroid biosynthesis. We examined (i) the PBR-cholesterol interaction by UV crosslinking of the C17 side-chain containing progestin, promegestone, and (ii) the role of the CRAC domain of PBR in Leydig cell steroidogenesis by using a transducible peptide composed of the TAT domain of HIV and the CRAC domain of PBR. [(3)H]Promegestone photoincorporated into recombinant PBR, and this labeling was displaced by cholesterol. [(3)H]Promegestone also photoincorporated into the TAT-CRAC peptide. [(3)H]Promegestone crosslinking to TAT-CRAC could be displaced by cholesterol and promegestone, with IC50 values of 1 and 200 microM, respectively. TAT-CRAC efficiently transduced into MA-10 Leydig cells and inhibited the hCG- and cAMP-stimulated steroid production in a dose-dependent manner. TAT-CRAC did not affect the hCG-induced cAMP synthesis and the 22R-hydroxycholesterol-supported steroidogenesis. Mutated TAT-CRAC lost its ability to bind [(3)H]promegestone and to inhibit the hCG-stimulated steroidogenesis. These results show that TAT-CRAC binds cholesterol and competes for cholesterol interaction with endogenous PBR, suggesting that the cytosolic carboxyl-terminal domain of PBR is responsible for taking up and bringing steroidogenic cholesterol into the mitochondria.

301 citations

Journal ArticleDOI
TL;DR: Both male and female null mice can be pharmacologically rescued by exogenous human chorionic gonadotropin, indicating that LH-responsiveness of the target cells is not irreversibly lost.
Abstract: Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) act on gonadal cells to promote steroidogenesis and gametogenesis Clarifying the in vivo roles of LH and FSH permits a feasible approach to contraception involving selective blockade of gonadotropin action One way to address these physiologically important problems is to generate mice with an isolated LH deficiency and compare them with existing FSH loss-of-function mice To model human reproductive disorders involving loss of LH function and to define LH-responsive genes, we produced knockout mice lacking the hormone-specific LHβ-subunit LHβ-null mice are viable but demonstrate postnatal defects in gonadal growth and function resulting in infertility Mutant males have decreased testes size, prominent Leydig cell hypoplasia, defects in expression of genes encoding steroid biosynthesis pathway enzymes, and reduced testosterone levels Furthermore, spermatogenesis is blocked at the round spermatid stage, causing a total absence of the elongated spermatids Mutant female mice are hypogonadal and demonstrate decreased levels of serum estradiol and progesterone Ovarian histology demonstrates normal thecal layer, defects in folliculogenesis including many degenerating antral follicles, and absence of corpora lutea The defects in both sexes are not secondary to aberrant FSH regulation, because FSH levels were unaffected in null mice Finally, both male and female null mice can be pharmacologically rescued by exogenous human chorionic gonadotropin, indicating that LH-responsiveness of the target cells is not irreversibly lost Thus, LHβ null mice represent a model to study the consequences of an isolated deficiency of LH ligand in reproduction, while retaining normal LH-responsiveness in target cells

297 citations

Journal ArticleDOI
TL;DR: Overall, the reviewed data underline the potential to identify specific types of responses to specific groups of chemicals such as EDs in order to develop suitable biomarkers that could be useful as diagnostic tools for endocrine disruption in marine invertebrates and vertebrates.
Abstract: Organic pollutants exhibiting endocrine disrupting activity (Endocrine Disruptors—EDs) are prevalent over a wide range in the aquatic ecosystems; most EDs are resistant to environmental degradation and are considered ubiquitous contaminants. The actual potency of EDs is low compared to that of natural hormones, but environmental concentrations may still be sufficiently high to produce detrimental biological effects. Most information on the biological effects and mechanisms of action of EDs has been focused on vertebrates. Here we summarize recent progress in studies on selected aspects of endocrine disruption in marine organisms that are still poorly understood and that certainly deserve further research in the near future. This review, divided in four sections, focuses mainly on invertebrates (effects of EDs and mechanisms of action) and presents data on top predators (large pelagic fish and cetaceans), a group of vertebrates that are particularly at risk due to their position in the food chain. The first section deals with basic pathways of steroid biosynthesis and metabolism as a target for endocrine disruption in invertebrates. In the second section, data on the effects and alternative mechanisms of action of estrogenic compounds in mussel immunocytes are presented, addressing to the importance of investigating full range responses to estrogenic chemicals in ecologically relevant invertebrate species. In the third section we review the potential use of vitellogenin (Vtg)-like proteins as a biomarker of endocrine disruption in marine bivalve molluscs, used worldwide as sentinels in marine biomonitoring programmes. Finally, we summarize the results of a recent survey on ED accumulation and effects on marine fish and mammals, utilizing both classical biomarkers of endocrine disruption in vertebrates and non-lethal techniques, such as non-destructive biomarkers, indicating the toxicological risk for top predator species in the Mediterranean. Overall, the reviewed data underline the potential to identify specific types of responses to specific groups of chemicals such as EDs in order to develop suitable biomarkers that could be useful as diagnostic tools for endocrine disruption in marine invertebrates and vertebrates.

284 citations

Journal ArticleDOI
TL;DR: In this chapter new facets of gonadal dysgenesis and novel defects in steroid biosynthesis are reviewed in relation to the DSD classification, and options for early, non-invasive fetal sexing are described.

272 citations

Journal ArticleDOI
TL;DR: The results of recent studies support the concept of an oligogenic disorder in which genes affecting metabolic pathways in glucose homeostasis and steroid biosynthesis are both involved and support the proposed interaction of a small number of key genes with environmental, particularly nutritional, factors.
Abstract: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. Familial clustering of cases suggests that genetic factors play an important part in its aetiology. A number of studies of families with several cases of PCOS have produced results suggesting an autosomal dominant trait. Detailed analysis of a large number of affected families has, however, cast some doubt about the mode of inheritance. An autosomal dominant trait remains possible but a more complex aetiology seems more likely. The results of our recent studies support the concept of an oligogenic disorder in which genes affecting metabolic pathways in glucose homeostasis and steroid biosynthesis are both involved. We review evidence for an important role for the insulin gene minisatellite in the aetiology of anovulatory PCOS and for the gene coding for P450 cholesterol side chain cleavage (CYP11a) in the mechanism of excessive androgen secretion in women with polycystic ovaries. We propose that the heterogeneity of clinical and biochemical features in PCOS can be explained by the interaction of a small number of key genes with environmental, particularly nutritional, factors.

271 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202315
202221
2021117
2020109
201975
201860