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https://www.readbyqxmd.com/read/28097086/liver-x-receptor-agonist-t0901317-reverses-resistance-of-a549-human-lung-cancer-cells-to-egfr-tki-treatment
#1
Haixia Cao, Shaorong Yu, Dan Chen, Changwen Jing, Zhuo Wang, Rong Ma, Siwen Liu, Jie Ni, Jifeng Feng, Jianzhong Wu
Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is effective in lung cancer patients carrying sensitive EGFR mutations. In this study, we investigated if liver X receptor (LXR) agonist T0901317 could reverse the resistance of lung cancer cell lines A549 and H1650 to EGFR-TKI treatment. We found that T0901317 could make natural EGFR-TKI-resistant A549 human lung cancer cells sensitive to EGFR-TKI treatment and that this was dependent on LXRβ expression. However, T0901317 does not have a similar effect on another natural EGFR-TKI-resistant cell line H1650...
January 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28091615/pirfenidone-controls-the-feedback-loop-of-the-at1r-p38-mapk-renin-angiotensin-system-axis-by-regulating-liver-x-receptor-%C3%AE-in-myocardial-infarction-induced-cardiac-fibrosis
#2
Chunmei Li, Rui Han, Le Kang, Jianping Wang, Yonglin Gao, Yanshen Li, Jie He, Jingwei Tian
Pirfenidone (PFD), an anti-fibrotic small molecule drug, is used to treat fibrotic diseases, but its effects on myocardial infarction (MI)-induced cardiac fibrosis are unknown. The aim of this study was to determine the effects of PFD on MI-induced cardiac fibrosis and the possible underlying mechanisms in rats. After establishment of the model, animals were administered PFD by gavage for 4 weeks. During the development of MI-induced cardiac fibrosis, we found activation of a positive feedback loop between the angiotensin II type 1 receptor (AT1R)/phospho-p38 mitogen-activated protein kinase (p38 MAPK) pathway and renin-angiotensin system (RAS), which was accompanied by down-regulation of liver X receptor-α (LXR-α) expression...
January 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28087808/identification-of-a-novel-liver-x-receptor-agonist-that-regulates-the-expression-of-key-cholesterol-homeostasis-genes-with-distinct-pharmacological-characteristics
#3
Ni Li, Xiao Wang, Yanni Xu, Yuan Lin, Ningyu Zhu, Peng Liu, Duo Lu, Shuyi Si
Activation of Liver X receptor (LXR) is associated with cholesterol metabolism and anti-inflammatory processes, which makes beneficial to anti-atherosclerosis. Nevertheless, existing agonists which target LXR, for example TO901317, are related to unwanted side-effects. In the present study, using a screening method we identified IMB-808, which displayed potent dual LXRα/β agonistic activity. In vitro, IMB-808 effectively increased the expressing quantity of genes related to reverse cholesterol transport process as well as those associated with cholesterol metabolism pathway in multiple cell lines...
January 13, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28086800/relevance-of-fxr-p62-sqstm1-pathway-for-survival-and-protection-of-mouse-hepatocytes-and-liver-especially-with-steatosis
#4
Sanae Haga, Yimin, Michitaka Ozaki
BACKGROUND: Liver injury and regeneration involve complicated processes and are affected by various physio-pathological conditions. Surgically, severe liver injury after surgical resection often leads to fatal liver failure, especially with some underlying pathological conditions such as steatosis. Therefore, protection from the injury of hepatocytes and liver is a serious concern in various clinical settings. METHODS: We studied the effects of the farnesoid X receptor (FXR) on cell survival and steatosis in mouse hepatocytes (AML12 mouse liver cells) and investigated their molecular mechanisms...
January 13, 2017: BMC Gastroenterology
https://www.readbyqxmd.com/read/28076928/rxr%C3%AE-is-upregulated-in-first-trimester-endometrial-glands-of-spontaneous-abortions-unlike-lxr-and-ppar%C3%AE
#5
J Knabl, A Vattai, R Hüttenbrenner, S Hutter, M Karsten, U Jeschke
Nuclear receptors are necessary for uterine invasion of the trophoblast and therefore important for maintaining a viable pregnancy. The aim of this study was to investigate the expression pattern and frequency of LXR, PPARγ and RXRα under physiological circumstances and in spontaneous abortions in endometrial glands and decidual tissue cells. A total of 28 (14 physiologic pregnancies/14 spontaneous abortion) human pregnancies in first trimester were analysed for expression of the nuclear receptors LXR, RXRα and PPARγ...
November 2, 2016: European Journal of Histochemistry: EJH
https://www.readbyqxmd.com/read/28070626/nuclear-receptors-regulate-lipid-metabolism-and-oxidative-stress-markers-in-chondrocytes
#6
Anusha Ratneswaran, Margaret Man-Ger Sun, Holly Dupuis, Cynthia Sawyez, Nica Borradaile, Frank Beier
: Joint homeostasis failure can result in osteoarthritis (OA). Currently, there are no treatments to alter disease progression in OA, but targeting early changes in cellular behavior has great potential. Recent data show that nuclear receptors contribute to the pathogenesis of OA and could be viable therapeutic targets, but their molecular mechanisms in cartilage are incompletely understood. This study examines global changes in gene expression after treatment with agonists for four nuclear receptor implicated in OA (LXR, PPARδ, PPARγ, and RXR)...
January 9, 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/28067791/ligands-of-therapeutic-utility-for-the-liver-x-receptors
#7
REVIEW
Rajesh Komati, Dominick Spadoni, Shilong Zheng, Jayalakshmi Sridhar, Kevin E Riley, Guangdi Wang
Liver X receptors (LXRs) have been increasingly recognized as a potential therapeutic target to treat pathological conditions ranging from vascular and metabolic diseases, neurological degeneration, to cancers that are driven by lipid metabolism. Amidst intensifying efforts to discover ligands that act through LXRs to achieve the sought-after pharmacological outcomes, several lead compounds are already being tested in clinical trials for a variety of disease interventions. While more potent and selective LXR ligands continue to emerge from screening of small molecule libraries, rational design, and empirical medicinal chemistry approaches, challenges remain in minimizing undesirable effects of LXR activation on lipid metabolism...
January 5, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28057729/lxr%C3%AE-and-lxr%C3%AE-nuclear-receptors-evolved-in-the-common-ancestor-of-gnathostomes
#8
Elza Fonseca, Raquel Ruivo, Mónica Lopes-Marques, Huixian Zhang, Miguel M Santos, Byrappa Venkatesh, L Filipe C Castro
Nuclear receptors (NRs) regulate numerous aspects of the endocrine system. They mediate endogenous and exogenous cues, ensuring a homeostatic control of development and metabolism. Gene duplication, loss and mutation have shaped the repertoire and function of NRs in metazoans. Here we examine the evolution of a pivotal orchestrator of cholesterol metabolism in vertebrates, the liver X receptors (LXRs). Previous studies suggested that LXRα and LXRβ genes emerged in the mammalian ancestor. However, we show through genome analysis and functional assay that bona fide LXRα and LXRβ orthologues are present in reptiles, coelacanth and chondrichthyans but not in cyclostomes...
January 4, 2017: Genome Biology and Evolution
https://www.readbyqxmd.com/read/28052875/liver-x-receptor-%C3%AE-lxr%C3%AE-increases-aqp2-protein-level-via-a-post-transcriptional-mechanism-in-renal-collecting-ducts
#9
Wen Su, Shi-Zheng Huang, Min Gao, Xiao-Mu Kong, Jan-Ake Gustafsson, Su-Juan Xu, Bing Wang, Feng Zheng, Li-Hong Chen, Nan-Ping Wang, You-Fei Guan, Xiao-Yan Zhang
Liver X Receptors (LXRs) including LXRα and LXRβ are nuclear receptor transcription factors and play an important role in lipid and glucose metabolism. It has been previously reported that mice lacking LXRβ but not LXRα develop a severe urine concentrating defect, likely via a central mechanism. Here we provide evidence that LXRβ regulates water homeostasis through increasing aquaporin 2 (AQP2) protein levels in renal collecting ducts. LXRβ-/- mice exhibited a reduced response to dDAVP stimulation, suggesting that the diabetes insipidus phenotype is of both central and nephrogenic origin...
January 4, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28041958/srebp1-contributes-to-resolution-of-pro-inflammatory-tlr4-signaling-by-reprogramming-fatty-acid-metabolism
#10
Yumiko Oishi, Nathanael J Spann, Verena M Link, Evan D Muse, Tobias Strid, Chantle Edillor, Matthew J Kolar, Takashi Matsuzaka, Sumio Hayakawa, Jenhan Tao, Minna U Kaikkonen, Aaron F Carlin, Michael T Lam, Ichiro Manabe, Hitoshi Shimano, Alan Saghatelian, Christopher K Glass
Macrophages play pivotal roles in both the induction and resolution phases of inflammatory processes. Macrophages have been shown to synthesize anti-inflammatory fatty acids in an LXR-dependent manner, but whether the production of these species contributes to the resolution phase of inflammatory responses has not been established. Here, we identify a biphasic program of gene expression that drives production of anti-inflammatory fatty acids 12-24 hr following TLR4 activation and contributes to downregulation of mRNAs encoding pro-inflammatory mediators...
December 21, 2016: Cell Metabolism
https://www.readbyqxmd.com/read/28039067/prenatal-betaine-exposure-alleviates-corticosterone-induced-inhibition-of-cyp27a1-expression-in-the-liver-of-juvenile-chickens-associated-with-its-promoter-dna-methylation
#11
Yun Hu, Qinwei Sun, Yibo Zong, Jie Liu, Abdulrahman A Idriss, Nagmeldin A Omer, Ruqian Zhao
Sterol 27-hydroxylase (CYP27A1) plays an important role in cholesterol homeostasis by degrading cholesterol to bile acids. Betaine can alleviate high-fat diet-induced hepatic cholesterol accumulation and maternal betaine treatment programs the hepatic expression of CYP27A1 in offspring. Excessive corticosterone (CORT) exposure causes hepatic cholesterol deposition in chickens, yet it remains unknown whether prenatal betaine modulates CORT-induced cholesterol accumulation in chicken liver later in life and whether it involves epigenetic gene regulation of CYP27A1...
December 27, 2016: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/28038938/regulation-of-the-expression-of-lxr-in-rat-hypothalamic-and-hippocampal-explants
#12
María Sol Kruse, Lucas Gabriel Suarez, Héctor Coirini
Liver X receptors (LXR) are important transcription factors involved in the regulation of carbohydrate and lipid metabolism and are expressed in different brain areas. Recently we described that LXR expression in the hypothalamus is sensitive to serum levels of lipids and carbohydrates. Here, we further characterized the effects of glucose, insulin, cholesterol and cholic acid on the expression of LXRα and LXRβ in hypothalamus and hippocampus explants as in vitro models. The LXR activation products, GLUT2 and ABCA1, were also analyzed by Western blot...
December 27, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/28034800/effects-of-tetramethylpyrazine-from-chinese-black-vinegar-on-antioxidant-and-hypolipidemia-activities-in-hepg2-cells
#13
Jicheng Chen, Jingjing Tian, Huifang Ge, Ruihai Liu, Jianbo Xiao
Tetramethylpyrazine is a bioactive compound found in Chinese black vinegar. This work is to investigate the potential effects of tetramethylpyrazine on intracellular cholesterol modulation in HepG2 cells. The results demonstrated that tetramethylpyrazine can induce intracellular cholesterol efflux. Tetramethylpyrazine may also improve endothelial function through its antioxidant effects by inhibiting reactive oxygen species levels and increasing the antioxidant enzymes superoxide dismutase and catalase. Tetramethylpyrazine increased liver X receptor and peroxisome proliferator-activated receptor gene expression in HepG2 cells...
December 26, 2016: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28034754/lxr-agonists-promote-the-proliferation-of-neural-progenitor-cells-through-mek-erk-pathway
#14
Jing-Zhong Wang, Yan Fang, Wei-Dong Ji, Hui Xu
The liver X receptors (LXRs) are transcriptional regulators of lipid homeostasis and may be critical for neurodegeneration and neurogenesis in vivo. However, it remains largely unknown about the role of LXRs and its agonists in the in vitro proliferation of neural progenitor cells (NPCs). Here we revealed for the first time that LXRs were markedly expressed in mouse NPCs and were critical for the in vitro proliferation. LXR agonists GW3965 and LXR623 promoted the proliferation of wildtype NPCs, but not NPCs from LXR double-knockout mice...
December 26, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28011707/fatty-acid-binding-profile-of-the-liver-x-receptor-alpha
#15
Shimpi Bedi, Genesis Victoria Hines, Valery V Lozada-Fernandez, Camila de Jesus Piva, Alagammai Kaliappan, S Dean Rider, Heather A Hostetler
Liver X receptor (LXR) alpha is a nuclear receptor that responds to oxysterols and cholesterol overload by stimulating cholesterol efflux, transport, conversion to bile acids, and excretion. LXR alpha binds to and is regulated by synthetic (T-0901317, GW3695) and endogenous (oxysterols) ligands. LXR alpha activity is also modulated by fatty acids (FA) but the ligand binding specificity of FA and acyl-CoA derivatives for LXR alpha remains unknown. We investigated whether LXR alpha binds FA or FA acyl-CoA with affinities that mimic in vivo concentrations, examined the effect of FA chain length and the degree of unsaturation on binding, and investigated if FA regulate LXR alpha activation...
December 23, 2016: Journal of Lipid Research
https://www.readbyqxmd.com/read/28011133/regulation-of-liver-x-receptor-target-genes-by-22-functionalized-oxysterols-synthesis-in-silico-and-in-vitro-evaluations
#16
Elvar Örn Viktorsson, Mari Gabrielsen, Nugalya Kumarachandran, Ingebrigt Sylte, Pål Rongved, Ove Alexander Høgmoen Åstrand, Eili Tranheim Kase
The endogenous oxysterol 22(R)-hydroxycholesterol (22RHC, 1) is an LXR agonist which upregulates genes of critical involvement in human cholesterol- and lipid metabolism. In contrast, its synthetic epimer 22(S)-hydroxycholesterol (22SHC, 8) has shown specific antagonistic effects in recent studies, avoiding unwanted side effects provided by potent LXR agonists. In terms of LXR modulation, the aim of this study was to compare 22SHC (8), 22RHC (1) and synthesized ligands with keto- and amide functionality in the 22nd position of the cholesterol scaffold...
December 21, 2016: Steroids
https://www.readbyqxmd.com/read/28009872/medium-chain-fatty-acids-reduce-serum-cholesterol-by-regulating-the-metabolism-of-bile-acid-in-c57bl-6j-mice
#17
Yinghua Liu, Yong Zhang, Xinsheng Zhang, Qing Xu, Xueyan Yang, Changyong Xue
Hypercholesterolemia is one of the important risk factors of atherosclerosis (AS). The aim of this study is to explore the effect of medium-chain fatty acids (MCFAs) on serum cholesterol levels and their mechanism of action. Hyperlipemia, as a model of abnormal lipid hypermetabolism, was established by using a high fat diet in C57BL/6J mice. Forty eight mice with dyslipidemia were randomly divided into 4 groups, 12 mice per group, including the control group, the 2% caprylic acid (C8:0)-treated group, 2% capric acid (C10:0)-treated group, and 2% oleic acid (C18:1)-treated group...
December 23, 2016: Food & Function
https://www.readbyqxmd.com/read/28002731/cholesterol-accumulation-in-cd11c-immune-cells-is-a-causal-and-targetable-factor-in-autoimmune-disease
#18
Ayaka Ito, Cynthia Hong, Kazuhiro Oka, Jon V Salazar, Cody Diehl, Joseph L Witztum, Mercedes Diaz, Antonio Castrillo, Steven J Bensinger, Lawrence Chan, Peter Tontonoz
Liver X receptors (LXRs) are regulators of cholesterol metabolism that also modulate immune responses. Inactivation of LXR α and β in mice leads to autoimmunity; however, how the regulation of cholesterol metabolism contributes to autoimmunity is unclear. Here we found that cholesterol loading of CD11c(+) cells triggered the development of autoimmunity, whereas preventing excess lipid accumulation by promoting cholesterol efflux was therapeutic. LXRβ-deficient mice crossed to the hyperlipidemic ApoE-deficient background or challenged with a high-cholesterol diet developed autoantibodies...
December 20, 2016: Immunity
https://www.readbyqxmd.com/read/27994765/discovery-of-highly-potent-liver-x-receptor-%C3%AE-agonists
#19
Ellen K Kick, Brett B Busch, Richard Martin, William C Stevens, Venkataiah Bollu, Yinong Xie, Brant C Boren, Michael C Nyman, Max H Nanao, Lam Nguyen, Artur Plonowski, Ira G Schulman, Grace Yan, Huiping Zhang, Xiaoping Hou, Meriah N Valente, Rangaraj Narayanan, Kamelia Behnia, A David Rodrigues, Barry Brock, James Smalley, Glenn H Cantor, John Lupisella, Paul Sleph, Denise Grimm, Jacek Ostrowski, Ruth R Wexler, Todd Kirchgessner, Raju Mohan
Introducing a uniquely substituted phenyl sulfone into a series of biphenyl imidazole liver X receptor (LXR) agonists afforded a dramatic potency improvement for induction of ATP binding cassette transporters, ABCA1 and ABCG1, in human whole blood. The agonist series demonstrated robust LXRβ activity (>70%) with low partial LXRα agonist activity (<25%) in cell assays, providing a window between desired blood cell ABCG1 gene induction in cynomolgus monkeys and modest elevation of plasma triglycerides for agonist 15...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27987394/liver-x-receptors-agonists-suppress-nlrp3-inflammasome-activation
#20
Shui-Xing Yu, Wei Chen, Xiao-Zhu Hu, Shi-Yuan Feng, Kun-Yu Li, Shuai Qi, Qian-Qian Lei, Gui-Qiu Hu, Ning Li, Feng-Hua Zhou, Chao-Ying Ma, Chong-Tao Du, Yong-Jun Yang
Inflammasomes are multiprotein complexes that control the production of IL-1β and IL-18. NLRP3 inflammasome, the most characterized inflammasome, plays prominent roles in defense against infection, however aberrant activation is deleterious and leads to diseases. Therefore, its tight control offers therapeutic promise. Liver X receptors (LXRs) have significant anti-inflammatory properties. Whether LXRs regulate inflammasome remains unresolved. We thus tested the hypothesis that LXR's anti-inflammatory properties may result from its ability to suppress inflammasome activation...
December 14, 2016: Cytokine
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