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Liver X Receptor

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https://www.readbyqxmd.com/read/28454103/subchronic-arsenism-induced-oxidative-stress-and-inflammatory-contribute-to-apoptosis-through-mitochondrial-and-death-receptor-dependent-pathways-in-chicken-immune-organs
#1
Hongjing Zhao, Ying He, Siwen Li, Xiao Sun, Yu Wang, Yizhi Shao, Zhijun Hou, Mingwei Xing
In many organ dysfunctions, arsenic and its compounds are well known to induce apoptosis by the mitochondria and death receptor apoptotic pathways in liver and airway. However, it is less reported that which signaling pathways contribute to excessive apoptosis of chicken immune organs, a major target of toxic metals biotransformation, which suffer from subchronic arsenism. In this study, we investigated whether the mitochondria or death receptor apoptotic pathways activated in the immune organs (spleen, thymus and bursa of Fabricius) of one-day-old male Hy-line chickens exposed to arsenic trioxide (As2O3), which were fed on diets supplemented with 0, 0...
April 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28453831/sortilin-1-loss-of-function-protects-against-cholestatic-liver-injury-by-attenuating-hepatic-bile-acid-accumulation-in-bile-duct-ligated-mice
#2
Jibiao Li, Benjamin L Woolbright, Wen Zhao, Yifeng Wang, David Matye, Bruno Hagenbuch, Hartmut Jaeschke, Tiangang Li
Sortilin 1 (Sort1) is an intracellular trafficking receptor that mediates protein sorting in the endocytic or secretory pathways. Recent studies revealed a role of Sort1 in the regulation of cholesterol and bile acid metabolism. This study further investigated the role of Sort1 in modulating bile acid detoxification and cholestatic liver injury in bile duct ligated mice. We found that Sort1 KO mice had attenuated liver injury 24 h after BDL, which was mainly attributed to less bile infarct formation. Sham-operated Sort1 KO mice had about 20% larger bile acid pool size than sham-operated WT mice, but 24 h after BDL Sort1 KO mice had significantly attenuated hepatic bile acid accumulation and smaller bile acid pool size...
April 26, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28449117/the-lxr-ligand-t0901317-acutely-inhibits-insulin-secretion-by-affecting-mitochondrial-metabolism
#3
Jonas Maczewsky, Jelena Sikimic, Cita Bauer, Peter Krippeit-Drews, Carmen Wolke, Uwe Lendeckel, Winfried Barthlen, Gisela Drews
The role of liver X receptor (LXR) in pancreatic beta-cell physiology and pathophysiology is still unclear. It has been postulated that chronic LXR activation in beta-cells induces lipotoxicity, a key step in the development of beta-cell dysfunction which accompanies type-2 diabetes mellitus. In most of these studies, the LXR ligand T0901317 has been administered chronically in the µmolar range to study the significance of LXR activation.In the present study, we have evaluated acute effects of T0901317 on stimulus-secretion coupling of beta-cells...
April 25, 2017: Endocrinology
https://www.readbyqxmd.com/read/28442922/inhibition-of-pcsk9-protects-against-radiation-induced-damage-of-prostate-cancer-cells
#4
Si-Shun Gan, Jian-Qing Ye, Lei Wang, Fa-Jun Qu, Chuan-Min Chu, Yi-Jun Tian, Wei Yang, Xin-Gang Cui
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein expressed primarily in the liver, formerly known to maintain plasma lipid homeostasis by regulating low-density lipoprotein receptor levels, and its exact role in the radioresistance of prostate cancer (PCa) remains unclear. We aim to investigate the function of PCSK9 in the radioresistance of PCa cells. METHODS: PCSK9 small interfering RNA (siRNA) was introduced into the PCa cells by transient transfection...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28442273/the-role-of-bile-acids-in-nonalcoholic-fatty-liver-disease-and-nonalcoholic-steatohepatitis
#5
REVIEW
Monica D Chow, Yi-Horng Lee, Grace L Guo
Nonalcoholic fatty liver disease is growing in prevalence worldwide. It is started by the presence of macrosteatosis on liver histology but is often clinically asymptomatic. However, it can progress into nonalcoholic steatohepatitis which is a more severe form of liver disease characterized by inflammation and fibrosis. Further progression leads to cirrhosis, which predisposes patients to hepatocellular carcinoma or liver failure. The mechanism by which simple steatosis progresses to steatohepatitis is not entirely clear...
April 22, 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28440421/allicin-induces-the-upregulation-of-abca1-expression-via-ppar%C3%AE-lxr%C3%AE-signaling-in-thp-1-macrophage-derived-foam-cells
#6
Xiao-Long Lin, Hui-Jun Hu, Yuan-Bo Liu, Xue-Mei Hu, Xiao-Juan Fan, Wei-Wen Zou, Yong-Quan Pan, Wen-Quan Zhou, Min-Wen Peng, Cai-Hong Gu
Allicin is considered anti-atherosclerotic due to its antioxidant and anti-inflammatory effects, which makes it an important drug for the prevention and treatment of atherosclerosis. However, the effects of allicin on foam cells are unclear. Thus, in this study, we examined the effects of allicin on lipid accumulation via peroxisome proliferator-activated receptor γ (PPARγ)/liver X receptor α (LXRα) in THP‑1 macrophage-derived foam cells. THP‑1 cells were exposed to 100 nM phorbol myristate acetate (PMA) for 24 h, and then to oxydized low-density lipoprotein (ox-LDL; 50 mg/ml) to induce foam cell formation...
April 11, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28436464/glucose-dependent-regulation-of-pregnane-x-receptor-is-modulated-by-amp-activated-protein-kinase
#7
Peter O Oladimeji, Wenwei Lin, C Trent Brewer, Taosheng Chen
Pregnane X receptor (PXR) is a xenobiotic receptor that regulates the detoxification and clearance of drugs and foreign compounds from the liver. There has been mounting evidence of crosstalk between the drug metabolism pathway and the energy metabolism pathway, but little is known about this cross-regulation. To further delineate the energy metabolism and drug metabolism crosstalk in this study, we exposed HepG2 cells to varying glucose concentrations. We observed that PXR activity was induced under high-glucose conditions...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28428138/pregnane-x-receptor-regulates-the-ahr-cyp1a1-pathway-and-protects-liver-cells-from-benzo-%C3%AE-pyrene-induced-dna-damage
#8
Hongmei Cui, Xinsheng Gu, Jingshu Chen, Ying Xie, Sui Ke, Jing Wu, Andrei Golovko, Benjamin Morpurgo, Chunhong Yan, Timothy D Phillips, Wen Xie, Jianyuan Luo, Zhijun Zhou, Yanan Tian
Pregnane X receptor (PXR) plays an important role in protecting cells from mutagenic DNA damages induced by endogenous and exogenous toxicants. This protective function is often attributed to the PXR-regulated metabolic detoxification. Here we report a novel potential mechanism that PXR reduces benzo-[α]-pyrene(BaP)-induced DNA damage through inhibiting the transcriptional activity of aryl hydrocarbon receptor (AhR) which plays a pivotal role in the bioactivation of BaP. We have utilized three well-characterized cell lines, i...
April 17, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28428116/cycloastragenol-improves-hepatic-steatosis-by-activating-farnesoid-x-receptor-signalling
#9
Ming Gu, Shiying Zhang, Yuanyuan Zhao, Jinwen Huang, Yahui Wang, Yin Li, Shengjie Fan, Li Yang, Guang Ji, Qingchun Tong, Cheng Huang
Non-alcoholic fatty liver disease (NAFLD) has become a global health problem. However, there is no approved therapy for NAFLD. Farnesoid X receptor (FXR) is a potential drug target for treatment of NAFLD. In an attempt to screen FXR agonists, we found that cycloastragenol (CAG), a natural occurring compound in Astragali Radix, stimulated FXR transcription activity. In animal studies, we demonstrated that CAG treatment resulted in obvious reduction of high-fat diet induced lipid accumulation in liver accompanied by lowered blood glucose, serum triglyceride levels and hepatic bile acid pool size...
April 18, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28427397/hvc1-ameliorates-hyperlipidemia-and-inflammation-in-ldlr-mice
#10
Se-Yun Cheon, Kyung-Sook Chung, Kyung-Jin Lee, Ho-Young Choi, In-Hye Ham, Dong-Hoon Jung, Yun-Yeop Cha, Hyo-Jin An
BACKGROUND: HVC1 consists of Coptidis Rhizoma (dried rhizome of Coptischinensis), Scutellariae Radix (root of Scutellariabaicalensis), Rhei Rhizoma (rhizome of Rheum officinale), and Pruni Cortex (cortex of Prunusyedoensis Matsum). Although the components are known to be effective in various conditions such as inflammation, hypertension, and hypercholesterolemia, there are no reports of the molecular mechanism of its hypolipidemic effects. METHODS: We investigated the hypolipidemic effect of HVC1 in low-density lipoprotein receptor-deficient (LDLR(-/-)) mice fed a high-cholesterol diet for 13 weeks...
April 20, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28424617/targeting-bile-acid-receptors-discovery-of-a-potent-and-selective-farnesoid-x-receptor-agonist-as-a-new-lead-in-the-pharmacological-approach-to-liver-diseases
#11
Carmen Festa, Simona De Marino, Adriana Carino, Valentina Sepe, Silvia Marchianò, Sabrina Cipriani, Francesco S Di Leva, Vittorio Limongelli, Maria C Monti, Angela Capolupo, Eleonora Distrutti, Stefano Fiorucci, Angela Zampella
Bile acid (BA) receptors represent well-defined targets for the development of novel therapeutic approaches to metabolic and inflammatory diseases. In the present study, we report the generation of novel C-3 modified 6-ethylcholane derivatives. The pharmacological characterization and molecular docking studies for the structure-activity rationalization, allowed the identification of 3β-azido-6α-ethyl-7α-hydroxy-5β-cholan-24-oic acid (compound 2), a potent and selective FXR agonist with a nanomolar potency in transactivation assay and high efficacy in the recruitment of SRC-1 co-activator peptide in Alfa Screen assay...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28422154/integration-of-liver-gene-co-expression-networks-and-egwas-analyses-highlighted-candidate-regulators-implicated-in-lipid-metabolism-in-pigs
#12
Maria Ballester, Yuliaxis Ramayo-Caldas, Manuel Revilla, Jordi Corominas, Anna Castelló, Jordi Estellé, Ana I Fernández, Josep M Folch
In the present study, liver co-expression networks and expression Genome Wide Association Study (eGWAS) were performed to identify DNA variants and molecular pathways implicated in the functional regulatory mechanisms of meat quality traits in pigs. With this purpose, the liver mRNA expression of 44 candidates genes related with lipid metabolism was analysed in 111 Iberian x Landrace backcross animals. The eGWAS identified 92 eSNPs located in seven chromosomal regions and associated with eight genes: CROT, CYP2U1, DGAT1, EGF, FABP1, FABP5, PLA2G12A, and PPARA...
April 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28421320/hepatocyte-specific-depletion-of-ubiquitin-regulatory-x-domain-containing-protein-8-accelerates-fibrosis-in-a-mouse-non-alcoholic-steatohepatitis-model
#13
Norihiro Imai, Michitaka Suzuki, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Kazuhiko Hayashi, Masatoshi Ishigami, Yoshiki Hirooka, Tetsuya Ishikawa, Hidemi Goto, Toyoshi Fujimoto
Ubiquitin regulatory X domain-containing protein 8 (UBXD8) is engaged in the degradation of lipidated apolipoprotein B in hepatocytes. We previously showed that hepatocyte-specific UBXD8-deficient mice (U8-HKO) fed a moderately high-fat diet (31 kcal % fat) showed periportal macrovesicular steatosis along with a decrease in very low-density lipoprotein secretion, but did not develop fibrosis. In the present study, we examined whether U8-HKO mice show NASH-like phenotypes when fed a very high-fat diet (60 kcal % fat)...
April 18, 2017: Histochemistry and Cell Biology
https://www.readbyqxmd.com/read/28420650/changes-in-lxr-signaling-influence-early-pregnancy-lipogenesis-and-protect-against-dysregulated-fetoplacental-lipid-homeostasis
#14
Vanya Nikolova, Georgia Papacleovoulou, Elena Bellafante, Luiza Borges Manna, Eugene Jansen, Silvère Baron, Shadi Abu-Hayyeh, Malcolm G Parker, Catherine Williamson
Human pregnancy is associated with enhanced de novo lipogenesis in the early stages followed by hyperlipidemia during advanced gestation. Liver X receptors (LXRs) are oxysterol-activated nuclear receptors which stimulate de novo lipogenesis and also promote the efflux of cholesterol from extrahepatic tissues followed by its transport back to the liver for biliary excretion. Although LXR is recognized as a master regulator of triglyceride and cholesterol homeostasis it is unknown whether it facilitates the gestational adaptations in lipid metabolism...
April 18, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28414139/ligand-dependent-and-independent-regulation-of-human-hepatic-sphingomyelin-phosphodiesterase-acid-like-3a-expression-by-pregnane-x-receptor-and-crosstalk-with-liver-x-receptor
#15
Judith Jeske, Andreas Bitter, Wolfgang E Thasler, Thomas S Weiss, Matthias Schwab, Oliver Burk
Pregnane X receptor (PXR) mainly regulates xenobiotic metabolism and detoxification. Additionally, it exerts pleiotropic effects on liver physiology, which in large parts depend on transrepression of other liver-enriched transcription factors. Based on the hypothesis that lower expression levels of PXR may reduce the extent of this inhibition, an exploratory genome-wide transcriptomic profiling was performed using HepG2 cell clones with different expression levels of PXR. This screen and confirmatory real-time RT-PCR identified sphingomyelin phosphodiesterase acid-like (SMPDL) 3A, a novel nucleotide phosphodiesterase and phosphoramidase, as being up-regulated by PXR-deficiency...
April 13, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28411380/metabolic-profile-of-obeticholic-acid-and-endogenous-bile-acids-in-rats-with-decompensated-liver-cirrhosis
#16
Aldo Roda, Rita Aldini, Cecilia Camborata, Silvia Spinozzi, Placido Franco, Massimiliano Cont, Antonia D'Errico, Francesco Vasuri, Alessio Degiovanni, Lorenzo Maroni, Luciano Adorini
Obeticholic acid (OCA) is a semisynthetic bile acid (BA) analogue and potent farnesoid X receptor agonist approved to treat cholestasis. We evaluated the biodistribution and metabolism of OCA administered to CCl4 -induced cirrhotic rats. This was to ascertain if plasma and hepatic concentrations of OCA are potentially more harmful than those of endogenous BA. After administration of OCA (30 mg/kg), we used liquid chromatography-mass spectrometry to measure OCA, its metabolites, and BA at different time-points in various organs and fluids...
April 14, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/28410994/the-role-of-oxysterols-in-human-cancer
#17
REVIEW
Alzbeta Kloudova, F Peter Guengerich, Pavel Soucek
Oxysterols are oxygenated derivatives of cholesterol formed in the human body or ingested in the diet. By modulating the activity of many proteins [e.g., liver X receptors (LXRs), oxysterol-binding proteins (OSBPs), some ATP-binding cassette (ABC) transporters], oxysterols can affect many cellular functions and influence various physiological processes (e.g., cholesterol metabolism, membrane fluidity regulation, intracellular signaling pathways). Therefore, the role of oxysterols is also important in pathological conditions (e...
April 12, 2017: Trends in Endocrinology and Metabolism: TEM
https://www.readbyqxmd.com/read/28406477/mir-21-ablation-and-obeticholic-acid-ameliorate-nonalcoholic-steatohepatitis-in-mice
#18
Pedro M Rodrigues, Marta B Afonso, André L Simão, Catarina C Carvalho, Alexandre Trindade, António Duarte, Pedro M Borralho, Mariana V Machado, Helena Cortez-Pinto, Cecília Mp Rodrigues, Rui E Castro
microRNAs were recently suggested to contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a disease lacking specific pharmacological treatments. In that regard, nuclear receptors are arising as key molecular targets for the treatment of nonalcoholic steatohepatitis (NASH). Here we show that, in a typical model of NASH-associated liver damage, microRNA-21 (miR-21) ablation results in a progressive decrease in steatosis, inflammation and lipoapoptosis, with impairment of fibrosis. In a complementary fast food (FF) diet NASH model, mimicking features of the metabolic syndrome, miR-21 levels increase in both liver and muscle, concomitantly with decreased expression of peroxisome proliferator-activated receptor α (PPARα), a key miR-21 target...
April 13, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28404878/activation-of-liver-x-receptor-delayed-the-retinal-degeneration-of-rd1-mice-through-modulation-of-the-immunological-function-of-glia
#19
Xiao He, Dayu Sun, Siyu Chen, Haiwei Xu
Retinal degeneration (RD), including retinitis pigmentosa (RP), is an inherited eye disease characterized by progressive degeneration of photoreceptors. Recently, immune cells, including microglia, Müller cells and astrocytes, in degenerative retina are demonstrated to play key roles in the development of RD and can be used as potential therapeutic targets. Liver X receptors (LXRs) are important immuno-inflammatory response transcription factors that have been reported to be a new potential therapeutic drug target for neurodegenerative diseases...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28400425/the-logic-of-transcriptional-regulator-recruitment-architecture-at-cis-regulatory-modules-controlling-liver-functions
#20
Julie Dubois-Chevalier, Vanessa Dubois, Hélène Dehondt, Parisa Mazrooei, Claire Mazuy, Aurélien A Sérandour, Céline Gheeraert, Guillaume Penderia, Eric Baugé, Bruno Derudas, Nathalie Hennuyer, Réjane Paumelle, Guillemette Marot, Jason S Carroll, Mathieu Lupien, Bart Staels, Philippe Lefebvre, Jérôme Eeckhoute
Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TR). However, how recruitment of a myriad of TR is orchestrated at cis-regulatory modules (CRM) to account for co-regulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRM involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question. Using integrative cistromic, epigenomic, transcriptomic and interactomic analyses, we reveal a logical organization where trans-regulatory modules (TRM), which consist of subsets of preferentially and co-ordinately co-recruited TR, assemble into hierarchical combinations at hepatic CRM...
April 11, 2017: Genome Research
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