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13 pages, 3221 KiB

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The Role of Adopted Orphan Nuclear Receptors in the Regulation of an Organic Anion Transporting Polypeptide 1B1 (OATP1B1) under the Action of Sex Hormones

by Aleksey V. Shchulkin, Yulia V. Abalenikhina, Aleksandr A. Slepnev, Egor D. Rokunov and Elena N. Yakusheva

Curr. Issues Mol. Biol. 2023, 45(12), 9593-9605; https://doi.org/10.3390/cimb45120600 - 29 Nov 2023

Cited by 5 | Viewed by 1559

Abstract

Organic anion transporting polypeptide 1B1 (OATP1B1) is an influx transporter protein of the SLC superfamily, expressed mainly in the liver and some tumor cells. The mechanisms of its regulation are being actively studied. In the present study, the effect of sex hormones (estradiol, progesterone and testosterone) on OATP1B1 expression in HepG2 cells was examined. The role of adopted orphan receptors, farnasoid X receptor (FXR), constitutive androstane receptor (CAR), pregnane X receptor (PXR) and liver X receptor subtype alpha (LXRa), was also evaluated. Hormones were used in concentrations of 1, 10 and 100 μM, with incubation for 24 h. The protein expression of OATP1B1, FXR, CAR, PXR and LXRa was analyzed by Western blot. It was shown that estradiol (10 and 100 μM) increased the expression of OATP1B1, acting through CAR. Testosterone (1, 10 and 100 μM) increased the expression of OATP1B1, acting through FXR, PXR and LXRa. Progesterone (10 and 100 μM) decreased the expression of OATP1B1 (10 and 100 μM) and adopted orphan receptors are not involved in this process. The obtained results have important practical significance and determine ways for targeted regulation of the transporter, in particular in cancer. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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14 pages, 3056 KiB

Open AccessArticle

GPR21 Inhibition Increases Glucose-Uptake in HepG2 Cells

by Gemma K. Kinsella, Stefania Cannito, Valentina Bordano, John C. Stephens, Arianna C. Rosa, Gianluca Miglio, Valeria Guaschino, Valeria Iannaccone, John B.C. Findlay and Elisa Benetti

Int. J. Mol. Sci. 2021, 22(19), 10784; https://doi.org/10.3390/ijms221910784 - 5 Oct 2021

Cited by 9 | Viewed by 4552

Abstract

GPR21 is a constitutively active, orphan, G-protein-coupled receptor, with in vivo studies suggesting its involvement in the modulation of insulin sensitivity. However, its precise contribution is not fully understood. As the liver is both a major target of insulin signalling and critically involved in glucose metabolism, the aim of this study was to examine the role of GPR21 in the regulation of glucose uptake and production in human hepatocytes. In particular, HepG2 cells, which express GPR21, were adopted as cellular models. Compared with untreated cells, a significant increase in glucose uptake was measured in cells treated with siRNA to downregulate GPR21 expression or with the GPR21-inverse agonist, GRA2. Consistently, a significantly higher membrane translocation of GLUT-2 was measured under these conditions. These effects were accompanied by an increased ratio of phAKT^(Ser473)/tot-AKT and phGSK-3β^(Ser9)/tot-GSK-3β, thus indicating a marked activation of the insulin signalling pathway. Moreover, a significant reduction in ERK activation was observed with GPR21 inhibition. Collectively, these results indicate that GPR21 mediates the negative effects on glucose uptake by the liver cells. In addition, they suggest that the pharmacological inhibition of GPR21 could be a novel strategy to improve glucose homeostasis and counteract hepatic insulin resistance. Full article

(This article belongs to the Special Issue Pharmacological Strategies for Metabolic Diseases: New Evidence)

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14 pages, 3814 KiB

Open AccessArticle

Molecular Mechanism of Action of RORγt Agonists and Inverse Agonists: Insights from Molecular Dynamics Simulation

by Nannan Sun, Congmin Yuan, Xiaojun Ma, Yonghui Wang, Xianfeng Gu and Wei Fu

Molecules 2018, 23(12), 3181; https://doi.org/10.3390/molecules23123181 - 3 Dec 2018

Cited by 19 | Viewed by 6986

Abstract

As an attractive drug-target, retinoic acid receptor-related orphan receptor-gamma-t (RORγt) has been employed widely to develop clinically relevant small molecular modulators as potent therapy for autoimmune disease and cancer, but its molecular mechanism of action (MOA) remains unclear. In the present study, we designed and discovered two novel RORγt ligands that are similar in structure, but different in efficacy. Using fluorescence resonance energy transfer (FRET) assay, compound 1 was identified as an agonist with an EC₅₀ of 3.7 μM (max. act.: 78%), while compound 2 as an inverse agonist with an IC₅₀ value of 2.0 μM (max. inh.: 61%). We performed molecular dynamics (MD) simulations, and elucidated the MOA of RORγt agonist and inverse agonist. Through the analyses of our MD results, we found that, after RORγt is bound with the agonist 1, the side chain of Trp317 stays in the gauche- conformation, and thus helps to form the hydrogen bond, His479-Trp502, and a large hydrophobic network among H11, H11′, and H12. All these interactions stabilize the H12, and helps the receptor recruit the coactivator. When the RORγt is bound with the inverse agonist 2, the side chain of Trp317 is forced to adopt the trans conformation, and these presumed interactions are partially destroyed. Taken together, the critical role of residue Trp317 could be viewed as the driving force for the activation of RORγt. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Symposium for Chinese Medicinal Chemists 2018)

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