The Experts below are selected from a list of 13719 Experts worldwide ranked by ideXlab platform
Shutsung Liao - One of the best experts on this subject based on the ideXlab platform.
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differential effects of activation of Liver X Receptor on plasma lipid homeostasis in wild type and lipoprotein clearance deficient mice
Atherosclerosis, 2010Co-Authors: Dacheng Peng, Richard A Hiipakka, Jingtian Xie, Catherine A Reardon, Godfrey S Getz, Shutsung LiaoAbstract:The effects of Liver X Receptor (LXR) agonists on plasma lipid homeostasis, especially triglyceride metabolism are controversial. Here we eXamined the effect of long-term activation of LXR on plasma lipid homeostasis in wild-type C57BL/6 and LDL Receptor deficient (LDLR−/−) mice given the LXR agonist T0901317 for 4 weeks. LXR agonist treatment of wild-type mice decreased plasma total triglycerides by 35% due to a significant reduction of plasma VLDL triglycerides. In contrast, in LDLR−/− mice T0901317 treatment increased plasma total cholesterol and triglycerides. An increase in the level of smaller VLDL particles was also observed in T0901317-treated LDLR−/− mice. The changes in circulating lipoprotein profiles in response to T0901317 treatment in these two animal models reflect the balance between synthesis and secretion on the one hand and lipolysis and clearance on the other. In both models there was both an increase in VLDL production and secretion and in an increase in LPL production and activity in T0901317-treated animals. In wild-type mice lipolysis and clearance predominates, while in the absence of the LDLR, which plays a major role in the clearance of apoB-containing lipoproteins, the increased output predominates. The generation of elevated levels of small VLDL particles due to increased lipolysis may represent an additional risk factor for atherosclerosis.
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the Liver X Receptor agonist t0901317 acts as androgen Receptor antagonist in human prostate cancer cells
Biochemical and Biophysical Research Communications, 2007Co-Authors: Chihpin Chuu, John M Kokontis, Richard A Hiipakka, Rouyu Chen, Karen V Warner, Jialing Xiang, Shutsung LiaoAbstract:T0901317 is a potent non-steroidal synthetic Liver X Receptor (LXR) agonist. T0901317 blocked androgenic stimulation of the proliferation of androgen-dependent LNCaP 104-S cells and androgenic suppression of the proliferation of androgen-independent LNCaP 104-R2 cells, inhibited the transcriptional activation of an androgen-dependent reporter gene by androgen, and suppressed gene and protein eXpression of prostate specific antigen (PSA), a target gene of androgen Receptor (AR) without affecting gene and protein eXpression of AR. T0901317 also inhibited binding of a radiolabeled androgen to AR, but inhibition was much weaker compared to the effect of the antiandrogens, bicalutamide and hydroXyflutamide. The LXR agonist T0901317, therefore, acts as an antiandrogen in human prostate cancer cells.
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antiproliferative effect of Liver X Receptor agonists on lncap human prostate cancer cells
Cancer Research, 2004Co-Authors: Junichi Fukuchi, John M Kokontis, Richard A Hiipakka, Chihpin Chuu, Shutsung LiaoAbstract:Liver X Receptors function as central transcriptional regulators for lipid homeostasis, for which agonists have been developed as potential drugs for treatment of cardiovascular diseases and metabolic syndromes. Because dysregulation of lipid metabolism has been implicated in seX hormone-dependent cancers, we investigated the effect of Liver X Receptor agonists on prostate and breast cancer cell proliferation. Treatment of human prostate cancer LNCaP cell lines with the synthetic Liver X Receptor agonist T0901317 decreased the percentage of S-phase cells in a dose-dependent manner and increased the eXpression of cyclin-dependent kinase inhibitor p27Kip-1 (p27). Knockdown of p27 by RNA interference blocks T0901317-induced growth inhibition, suggesting that p27 eXpression plays a crucial role in this signaling. Liver X Receptor agonists also inhibited the proliferation of other prostate and breast cancer cell lines. The level of Liver X Receptor α eXpression correlated directly with sensitivity to growth inhibition by Liver X Receptor agonists. Retroviral eXpression of Liver X Receptor α in human breast cancer MDA-MB435S cells, which eXpress low levels of endogenous Liver X Receptors and are insensitive to T0901317, sensitized these cells to T0901317. Consistent with our observations in LNCaP cells, T0901317 induces dramatic up-regulation of p27 in Liver X Receptor α–overeXpressing MDA-MB435S cells. Furthermore, oral administration of T0901317 inhibited the growth of LNCaP tumors in athymic nude mice. Based on these results, modulation of the Liver X Receptor signaling pathway is a new target for controlling tumor cell proliferation; therefore, Liver X Receptor agonists may have utility as antitumorigenic agents.
Guangping Chen - One of the best experts on this subject based on the ideXlab platform.
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Liver X Receptor alpha mediated genistein induction of human dehydroepiandrosterone sulfotransferase hsult2a1 in hep g2 cells
Toxicology and Applied Pharmacology, 2013Co-Authors: Shunfen Zhang, Alicia Mclaughlin, Guangping ChenAbstract:Cytosolic sulfotransferases are one of the major families of phase II drug metabolizing enzymes. Sulfotransferase-catalyzed sulfonation regulates hormone activities, metabolizes drugs, detoXifies Xenobiotics, and bioactivates carcinogens. Human dehydroepiandrosterone sulfotransferase (hSULT2A1) plays important biological roles by sulfating endogenous hydroXysteroids and eXogenous Xenobiotics. Genistein, mainly eXisting in soy food products, is a naturally occurring phytoestrogen with both chemopreventive and chemotherapeutic potential. Our previous studies have shown that genistein significantly induces hSULT2A1 in Hep G2 and Caco-2 cells. In this study, we investigated the roles of Liver X Receptor (LXRα) in the genistein induction of hSULT2A1. LXRs have been shown to induce eXpression of mouse Sult2a9 and hSULT2A1 gene. Our results demonstrate that LXRα mediates the genistein induction of hSULT2A1, supported by Western blot analysis results, hSULT2A1 promoter driven luciferase reporter gene assay results, and mRNA interference results. Chromatin immunoprecipitation (ChIP) assay results demonstrate that genistein increase the recruitment of hLXRα binding to the hSULT2A1 promoter. These results suggest that hLXRα plays an important role in the hSULT2A1 gene regulation. The biological functions of phytoestrogens may partially relate to their induction activity toward hydroXysteroid SULT.
Pércio S. Gulko - One of the best experts on this subject based on the ideXlab platform.
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Liver X Receptor regulates rheumatoid arthritis fibroblast like synoviocyte invasiveness matriX metalloproteinase 2 activation interleukin 6 and cXcl10
Molecular Medicine, 2012Co-Authors: Teresina Laragione, Pércio S. GulkoAbstract:Fibroblast-like synoviocyte (FLS) invasiveness correlates with articular damage in rheumatoid arthritis (RA), yet little is known about its regulation. In this study we aimed to determine the role of the nuclear Receptor Liver X Receptor (LXR) in FLS invasion. FLS were isolated from synovial tissues obtained from RA patients and from DA rats with pristane-induced arthritis. Invasion was tested on Matrigel-coated chambers in the presence of the LXR agonist T0901317, or control vehicle. FLS were cultured in the presence or absence of T0901317, and supernatants were used to quantify matriX metalloproteinase 1 (MMP-1), MMP-2, MMP-3, interleukin-6 (IL-6), tumor necrosis factor-α and C-X-C motif chemokine ligand 10 (CXCL10). Nuclear factor-κB (NF-κB) (p65) and Akt activation, actin cytoskeleton, cell morphology and lamellipodia formation were also determined. The LXR agonist T0901317 significantly reduced DA FLS invasion by 99% (P ≤ 0.001), and RA FLS invasion by 96% (P ≤ 0.001), compared with control. T0901317-induced suppression of invasion was associated with reduced production of activated MMP-2, IL-6 and CXCL10 by RA FLS, and with reduction of actin filament reorganization and reduced polarized formation of lamellipodia. T0901317 also prevented both IL-1β-induced and IL-6-induced FLS invasion. NF-κB (p65) and Akt activation were not significantly affected by T0901317. This is the first description of a role for LXR in the regulation of FLS invasion and in processes and pathways implicated both in invasion as well as in inflammatory responses. These findings provide a new rationale for considering LXR agonists as therapeutic agents aimed at reducing both inflammation and FLS-mediated invasion and destruction in RA.
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MOESM1 of Liver X Receptor Regulates Rheumatoid Arthritis Fibroblast-like Synoviocyte Invasiveness, MatriX Metalloproteinase 2 Activation, Interleukin-6 and CXCL10
2012Co-Authors: Teresina Laragione, Pércio S. GulkoAbstract:Liver X Receptor Regulates Rheumatoid Arthritis Fibroblast-like Synoviocyte Invasiveness, MatriX Metalloproteinase 2 Activation, Interleukin-6 and CXCL1
Richard A Hiipakka - One of the best experts on this subject based on the ideXlab platform.
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the effect of diet on the response of low density lipoprotein Receptor knockout mice to the Liver X Receptor agonist t1317
Journal of Cardiovascular Pharmacology, 2011Co-Authors: Lu Peng, Richard A Hiipakka, Jingtian Xie, John M Kokontis, Shutsung Liao, Dacheng PengAbstract:Abstract:It has been previously observed that low-density lipoprotein Receptor knockout (LDLR−/−) mice fed a Western-type diet without cholate and given the Liver X Receptor agonist T1317 develop a persistent and enhanced hypertriglyceridemia. In contrast, LDLR−/− mice fed a Paigen diet with cholate
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differential effects of activation of Liver X Receptor on plasma lipid homeostasis in wild type and lipoprotein clearance deficient mice
Atherosclerosis, 2010Co-Authors: Dacheng Peng, Richard A Hiipakka, Jingtian Xie, Catherine A Reardon, Godfrey S Getz, Shutsung LiaoAbstract:The effects of Liver X Receptor (LXR) agonists on plasma lipid homeostasis, especially triglyceride metabolism are controversial. Here we eXamined the effect of long-term activation of LXR on plasma lipid homeostasis in wild-type C57BL/6 and LDL Receptor deficient (LDLR−/−) mice given the LXR agonist T0901317 for 4 weeks. LXR agonist treatment of wild-type mice decreased plasma total triglycerides by 35% due to a significant reduction of plasma VLDL triglycerides. In contrast, in LDLR−/− mice T0901317 treatment increased plasma total cholesterol and triglycerides. An increase in the level of smaller VLDL particles was also observed in T0901317-treated LDLR−/− mice. The changes in circulating lipoprotein profiles in response to T0901317 treatment in these two animal models reflect the balance between synthesis and secretion on the one hand and lipolysis and clearance on the other. In both models there was both an increase in VLDL production and secretion and in an increase in LPL production and activity in T0901317-treated animals. In wild-type mice lipolysis and clearance predominates, while in the absence of the LDLR, which plays a major role in the clearance of apoB-containing lipoproteins, the increased output predominates. The generation of elevated levels of small VLDL particles due to increased lipolysis may represent an additional risk factor for atherosclerosis.
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the Liver X Receptor agonist t0901317 acts as androgen Receptor antagonist in human prostate cancer cells
Biochemical and Biophysical Research Communications, 2007Co-Authors: Chihpin Chuu, John M Kokontis, Richard A Hiipakka, Rouyu Chen, Karen V Warner, Jialing Xiang, Shutsung LiaoAbstract:T0901317 is a potent non-steroidal synthetic Liver X Receptor (LXR) agonist. T0901317 blocked androgenic stimulation of the proliferation of androgen-dependent LNCaP 104-S cells and androgenic suppression of the proliferation of androgen-independent LNCaP 104-R2 cells, inhibited the transcriptional activation of an androgen-dependent reporter gene by androgen, and suppressed gene and protein eXpression of prostate specific antigen (PSA), a target gene of androgen Receptor (AR) without affecting gene and protein eXpression of AR. T0901317 also inhibited binding of a radiolabeled androgen to AR, but inhibition was much weaker compared to the effect of the antiandrogens, bicalutamide and hydroXyflutamide. The LXR agonist T0901317, therefore, acts as an antiandrogen in human prostate cancer cells.
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antiproliferative effect of Liver X Receptor agonists on lncap human prostate cancer cells
Cancer Research, 2004Co-Authors: Junichi Fukuchi, John M Kokontis, Richard A Hiipakka, Chihpin Chuu, Shutsung LiaoAbstract:Liver X Receptors function as central transcriptional regulators for lipid homeostasis, for which agonists have been developed as potential drugs for treatment of cardiovascular diseases and metabolic syndromes. Because dysregulation of lipid metabolism has been implicated in seX hormone-dependent cancers, we investigated the effect of Liver X Receptor agonists on prostate and breast cancer cell proliferation. Treatment of human prostate cancer LNCaP cell lines with the synthetic Liver X Receptor agonist T0901317 decreased the percentage of S-phase cells in a dose-dependent manner and increased the eXpression of cyclin-dependent kinase inhibitor p27Kip-1 (p27). Knockdown of p27 by RNA interference blocks T0901317-induced growth inhibition, suggesting that p27 eXpression plays a crucial role in this signaling. Liver X Receptor agonists also inhibited the proliferation of other prostate and breast cancer cell lines. The level of Liver X Receptor α eXpression correlated directly with sensitivity to growth inhibition by Liver X Receptor agonists. Retroviral eXpression of Liver X Receptor α in human breast cancer MDA-MB435S cells, which eXpress low levels of endogenous Liver X Receptors and are insensitive to T0901317, sensitized these cells to T0901317. Consistent with our observations in LNCaP cells, T0901317 induces dramatic up-regulation of p27 in Liver X Receptor α–overeXpressing MDA-MB435S cells. Furthermore, oral administration of T0901317 inhibited the growth of LNCaP tumors in athymic nude mice. Based on these results, modulation of the Liver X Receptor signaling pathway is a new target for controlling tumor cell proliferation; therefore, Liver X Receptor agonists may have utility as antitumorigenic agents.
Jason Matthews - One of the best experts on this subject based on the ideXlab platform.
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Liver X Receptor regulates hepatic nuclear o glcnac signaling and carbohydrate responsive element binding protein activity
Journal of Lipid Research, 2015Co-Authors: Christian Bindesboll, Knut R Steffensen, Qiong Fan, Rikke Christine Norgaard, Laura Macpherson, Hai Bin Ruan, Thomas Aarskov Pedersen, Xiaoyong Yang, Jason MatthewsAbstract:Liver X Receptor (LXR)α and LXRβ play key roles in hepatic de novo lipogenesis through their regulation of lipogenic genes, including sterol regulatory element-binding protein (SREBP)-1c and carbohydrate responsive element-binding protein (ChREBP). LXRs activate lipogenic gene transcription in response to feeding, which is believed to be mediated by insulin. We have previously shown that LXRs are targets for glucose-heXosamine-derived O-linked β-N-acetylglucosamine (O-GlcNAc) modification enhancing their ability to regulate SREBP-1c promoter activity in vitro. To elucidate insulin-independent effects of feeding on LXR-mediated lipogenic gene eXpression in vivo, we subjected control and streptozotocin-treated LXRα/β+/+ and LXRα/β−/− mice to a fasting-refeeding regime. We show that under hyperglycemic and hypoinsulinemic conditions, LXRs maintain their ability to upregulate the eXpression of glycolytic and lipogenic enzymes, including glucokinase (GK), SREBP-1c, ChREBPα, and the newly identified shorter isoform ChREBPβ. Furthermore, glucose-dependent increases in LXR/retinoid X Receptor-regulated luciferase activity driven by the ChREBPα promoter was mediated, at least in part, by O-GlcNAc transferase (OGT) signaling in Huh7 cells. Moreover, we show that LXR and OGT interact and colocalize in the nucleus and that loss of LXRs profoundly reduced nuclear O-GlcNAc signaling and ChREBPα promoter binding activity in vivo. In summary, our study provides evidence that LXRs act as nutrient and glucose metabolic sensors upstream of ChREBP by modulating GK eXpression, nuclear O-GlcNAc signaling, and ChREBP eXpression and activity.