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The Stimulation of Steroid Biosynthesis by Luteinizing Hormone
Published in Mario Ascoli, Luteinizing Hormone Action and Receptors, 2019
Anita H. Payne, Patrick G. Quinn, John R. D. Stalvey
Testosterone production in the presence of 25- or 22R-hydroxycholesterol is greater than LH-stimulated testosterone production in rat Leydig cells,127 indicating that these compounds gain access to the mitochondria in these cells as well. Metabolism of these hydroxysterols was slightly but significantly increased by preincubation of Leydig cells with an LHRH agonist, and was insensitive to cycloheximide. Thus, it would appear that metabolism of hydroxysterols may be an accurate indication of the amount of P-450scc in rat Leydig and luteal cells, and therefore provide an estimation of the maximal steroidogenic capacity of these cells in vitro.
Inhibiting Insulin Resistance and Accumulation of Triglycerides and Cholesterol in the Liver
Published in Christophe Wiart, Medicinal Plants in Asia for Metabolic Syndrome, 2017
Oxysterols such as 22(R)-hydroxycholesterol derived from cholesterol in the liver, bind to and activate liver X receptor which heterodimerizes with 9-cis retinoid acid-activated retinoid X receptor.114 This nuclear receptor and transcription factor controls the expression of cholesterol 7α-hydroxylase (CYP7A1), sterol regulatory-binding element protein-1c in the liver, ABCA1, and G1 and apolipoprotrein E in macrophages.115 Liver X receptor serves also as a glucose sensor and regulates the expression of phosphoenol carboxykinase, glucose-6-phosphatase, and glucokinase.116 In adipose tissues, liver X receptor induces the expression of glucose transporter type 4 explaining why liver X receptor agonists improve insulin sensitivity.117 Rhein from Rheum palmatum L. is an antagonist of liver X receptor-α which Kd values of 46.7 µM.118 In HepG2, this anthraquinone at a concentration of 25 µM inhibited the expression of adenosine triphosphate-binding cassette protein A1 ABC transporter G1, sterol regulatory element binding protein-1c, fatty acid synthetase, stearoyl coenzyme A desaturase 1, and acetyl-CoA carboxylase induced by liver X receptor agonist GW3965 in vitro.118 Liver X receptor-α antagonism by rhein could at least partially account to the fact that C57BL/6J mice fed a high-fat diet given for 4 weeks, rhein decreased the expression of sterol regulatory element binding protein-1c, fatty acid synthetase, stearoyl coenzyme A desaturase 1 and acetyl-CoA carboxylase and triphosphate-binding cassette protein-A1.118 In hepatocyte, this anthraquinone increased glucose transporter-2 and decreased 3-hydroxy-3-methylglutaryl-coenzyme A reductase expression.118
Factors Controlling the Biosynthesis of Aldosterone
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
The cholesterol side-chain cleavage reaction takes place in mitochondria in the presence of molecular oxygen with NADPH as the reducing agent. The bioconversion of cholesterol to pregnenolone in adrenocortical tissue is regarded by many workers as a control point for corticosteroid biosynthesis. Accordingly, many efforts have been made to elucidate the details of the mechanism of this transformation, and a number of controversial hypotheses have been proposed. The classical approach depicts the side-chain cleavage as proceeding through a sequential, mixed-function oxidase with 20α- and 22R-hydroxylations of cholesterol to form 20α, 22R-dihydroxycholesterol via either the 20α- or 22R-hydroxycholesterol, with scission of the C20-C22 bond of the 20α, 22R-glycol by a separate lyase yielding pregnenolone and isocaproicaldehyde.29 Other intermediates leading to the 20α, 22R-glycol which have been proposed include the 20-hydroperoxycholesterol30 and the 20, 22-epoxycholesterol.31 However, the hydroperoxide route has been precluded by 18O studies32 whereas putative dehydro- and epoxy-intermediates are ruled out by metabolic studies on synthetic substrates.33,34 Difficulties in detecting any intermediates at all during cholesterol incubations suggest that side-chain cleavage involves a concerted type of reaction from which only pregnenolone is released in the medium.29,35 Consistent with this concept is the postulate that the true intermediates are not stable products, but rather, that they are transient, reactive radical, or ionic species.36 However, recent kinetic studies by Burstein and Gut37 on the early formation of intermediates during adrenocortical incubations with cholesterol strongly suggest that the sequence 22R-OH → 20α, 22R-diOH → pregnenolone is the basic route by which side-chain cleavage in the adrenal cortex takes place. These observations are in agreement with the scheme for side-chain cleavage recently proposed by van Lier et al.38,39 Their system provides a model in which the epimeric 20-hydroperoxycholesterols serve both as substrate and as source of the “activated” oxygen, resulting in stereospecific hydroperoxide-glycol rearrangements. Based on such findings, they propose that the side-chain cleavage of cholesterol involves three consecutive in situ oxidations through a ferryl-atomic oxygen complex of P-450 with pregnenolone as the final product (Figure 3). Using purified enzyme preparations, Morisaki et al.,40 also obtained evidence suggesting that the three steps involve a single species of cytochrome P-450.
Standardizing and increasing the utility of lipidomics: a look to the next decade
Published in Expert Review of Proteomics, 2020
Yuqin Wang, Eylan Yutuc, William J Griffiths
Another important oxysterol is 24S-hydroxycholesterol (24S-HC). In human, 24S-HC is the dominant diastereoisomer, although 24 R-HC is also present in plasma at much low levels Figure 5B. 24S-HC and 24R-HC are often unresolved in GC-MS and LC-MS experiments and ‘biological intelligence’ is invoked to characterize the oxysterol identified as the 24S-epimer. The geometrical similarity of 24S-HC, 24R-HC, 25-HC, (25R)26-hydroxycholesterol ((25R)26-HC, also known as 27-hydroxycholesterol) and of 22R-hydroxycholesterol, all of which are present in plasma at different levels makes their chromatographic separation challenging (see Figure 5 and also [109]). This challenge is accentuated in LC-MS/MS studies by the similarity of their MS/MS spectra which, in the absence of derivatization, are dominated by the loss of one or two molecules of water (see [117] and [118] for reference spectra). An advantage of the Girard P derivatization method used by Blanc et al [111], as developed by Griffiths and Wang [53,98,103,105,119,120], is that the derivatizing group which ‘charge-tags’ the analyte directs fragmentation resulting in MS3 spectra that are different for different oxysterol isomers. This in combination with enhanced solubility in reversed-phase solvents allows the determination of essentially all monohydroxycholesterol isomers Figure 5.
Nuclear receptor ligands induce TREM-1 expression on dendritic cells: analysis of their role in tumors
Published in OncoImmunology, 2019
Raffaella Fontana, Laura Raccosta, Lucrezia Rovati, Knut R. Steffensen, Aida Paniccia, Tomas Jakobsson, Giulio Melloni, Alessandro Bandiera, Giorgia Mangili, Alice Bergamini, Daniela Maggioni, Claudio Doglioni, Roberto Crocchiolo, Marina Cella, Michela Mattioli, Cristina Battaglia, Marco Colonna, Vincenzo Russo
Here, we report on the identification of TREM-1 as a new target of different nuclear receptors, i.e. LXRs, RXRs, RARs and VDR. By transcriptomic studies we show TREM-1 expression on maturing DCs treated with the oxysterol 22R-Hydroxycholesterol (22R-HC). Moreover, we demonstrate that retinoids (RXR and RAR ligands) strongly induce TREM-1 expression, which once triggered by anti-TREM-1 mAb, induces the release of high amounts of the pro-inflammatory cytokines IL-1β and TNFα by myeloid DCs. We also provide evidence that TREM-1 is expressed on a subset of so-called inflammatory DCs, ex vivo isolated from pleural and peritoneal fluids of advanced cancer patients. These results pave the way to the elucidation of this pathway in inflammation and inflammation-driven diseases.
FXR modulators for enterohepatic and metabolic diseases
Published in Expert Opinion on Therapeutic Patents, 2018
Hong Wang, Qingxian He, Guangji Wang, Xiaowei Xu, Haiping Hao
BA pool includes the primary BAs, CA and CDCA, and secondary BAs, DCA and LCA, and their taurine or glycine conjugates. Interestingly, the potency of various BA species to activate FXR is CDCA>DCA>LCA>CA. The structures-activity relationship (SAR) analysis indicated that the replacement in position 3 and 7 of BA skeleton as well as the side chain is important for the FXR agonism [5]. Since the hydrophobic CDCA is the most potent natural activator, with an EC50 of 50 μM and 10 μM on murine and human FXR, respectively, a panel of semi-synthetic derivatives upon modification on CDCA have been generated to further clarify SAR and generate highly potent agonists. Substitution of the carboxylic group on the side chain with amino, carbamate, sulfate or sulfonate can achieve full agonism or partial antagonism. 3α-hydroxyl group has marginal effect on its activity, while 6α-alkyl substitution significantly improves its potency and efficacy on FXR, consistent with the very hydrophobic nature of the pocket in FXR complementary to the 6α position [45,46]. Introduction of an ethyl at 6 position of CDCA yields 6α-ethyl-chenodeoxycholic acid (6-ECDCA/INT-747/OCA), with an remarkable improvement on potency and the EC50 value at 99 nM [47]. Intercept Pharmaceuticals owns 6 US patents, 4 pending US patent applications and corresponding foreign patents and patent applications for OCA [48–50]. INT-767, a sulfate homologue of OCA, has been described as a slightly higher potent FXR agonist with an EC50 value of 30 nM [51,52]. Modification at both position 6 and side chain led to the discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihyfroxy-6α-ethyl-24-nor-5β-cholan-23-amine, which showed higher FXR agonism efficiency in comparison with OCA [53]. NIHS700 [54] and TC-100 (3α,7α,11β-trihydroxy-6α-ethyl-5β-cholan-24-oic acid) [55], another two BA derivatives have also been developed as FXR agonists. Additionally, 22(R)-hydroxycholesterol [22(R)-OHC], an intermediate in the biotransformation of cholesterol to BAs [56], has also been identified as FXR agonist.