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https://www.readbyqxmd.com/read/28324010/separating-the-anti-inflammatory-and-diabetogenic-effects-of-glucocorticoids-through-lxr%C3%AE-antagonism
#1
Rucha Patel, Lilia Magomedova, Ricky Tsai, Stéphane Angers, Arturo Orellana, Carolyn L Cummins
Synthetic glucocorticoids (GCs) including dexamethasone (DEX) are powerful anti-inflammatory drugs. Long-term use of GCs, however, can result in metabolic side effects such as hyperglycemia, hepatosteatosis, and insulin resistance. The glucocorticoid receptor (GR) and liver X receptors (LXRα and LXRβ) regulate overlapping genes involved in gluconeogenesis and inflammation. We have previously shown that Lxrβ-/- mice are resistant to the diabetogenic effects of DEX, but still sensitive to its immunosuppressive actions...
January 27, 2017: Endocrinology
https://www.readbyqxmd.com/read/28315462/implications-of-cerebrovascular-atp-binding-cassette-transporter-g1-abcg1-and-apolipoprotein-m-in-cholesterol-transport-at-the-blood-brain-barrier
#2
Alexandra Carmen Kober, Anil Paul Chirackal Manavalan, Carmen Tam-Amersdorfer, Andreas Holmér, Ahmed Saeed, Elham Fanaee Danesh, Martina Zandl, Nicole Maria Albrecher, Ingemar Björkhem, Gerhard M Kostner, Björn Dahlbäck, Ute Panzenboeck
Impaired cholesterol/lipoprotein metabolism is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Cerebral cholesterol homeostasis is maintained by the highly efficient blood-brain barrier (BBB) and flux of the oxysterols 24(S)-hydroxycholesterol and 27-hydroxycholesterol, potent liver-X-receptor (LXR) activators. HDL and their apolipoproteins are crucial for cerebral lipid transfer, and loss of ATP binding cassette transporters (ABC)G1 and G4 results in toxic accumulation of oxysterols in the brain...
March 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28300583/synthesis-of-new-c-25-and-c-26-steroidal-acids-as-potential-ligands-of-the-nuclear-receptors-daf-12-lxr-and-gr
#3
María V Dansey, María C Del Fueyo, Adriana S Veleiro, Pablo H Di Chenna
A new methodology to obtain C-25 and C-26 steroidal acids starting from pregnenolone is described. Construction of the side chain was achieved by applying the Mukaiyama aldol reaction with a non-hydrolytic work-up to isolate the trapped silyl enol ether with higher yields. Using this methodology we synthesized three new steroidal acids as potential ligands of DAF-12, Liver X and Glucocorticoid nuclear receptors and studied their activity in reporter gene assays. Our results show that replacement of the 21-CH3 by a 20-keto group in the side chains of the cholestane scaffold of DAF-12 or Liver X receptors ligands causes the loss of the activity...
March 11, 2017: Steroids
https://www.readbyqxmd.com/read/28296229/phytosterol-mediated-inhibition-of-intestinal-cholesterol-absorption-in-mice-is-independent-of-liver-x-receptor
#4
Lídia Cedó, David Santos, Iziar A Ludwig, Reija Silvennoinen, Annabel García-León, Leena Kaipiainen, José M Carbó, Annabel F Valledor, Helena Gylling, Maria-José Motilva, Petri T Kovanen, Miriam Lee-Rueckert, Francisco Blanco-Vaca, Joan Carles Escolà-Gil
SCOPE: Previous studies have proposed that phytosterols activate liver X receptors (LXR) in the intestine, thereby reducing intestinal cholesterol absorption and promoting fecal cholesterol excretion. METHODS AND RESULTS: In the present study, we examined the effects of dietary phytosterol supplementation on intestinal cholesterol absorption and fecal neutral sterol excretion in LXRαβ-deficient mice, and wild-type mice treated with synthetic high-affinity LXRαβ agonists...
March 15, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/28273782/active-liver-x-receptor-signaling-in-phagocytes-in-multiple-sclerosis-lesions
#5
Jo Mailleux, Tim Vanmierlo, Jeroen Fj Bogie, Elien Wouters, Dieter Lütjohann, Jerome Ja Hendriks, Jack van Horssen
OBJECTIVE: We sought to determine the liver X receptor (LXR) ligands present in human macrophages after myelin phagocytosis and whether LXRs are activated in multiple sclerosis (MS) lesions. METHODS: We used real-time quantitative polymerase chain reaction (PCR) and immunohistochemistry to determine expression of LXRs and their response genes in human phagocytes after myelin phagocytosis and in active MS lesions. We used gas chromatographic/mass spectrometric analysis to determine LXR-activating oxysterols and cholesterol precursors present and formed in myelin and myelin-incubated cells, respectively...
February 1, 2017: Multiple Sclerosis: Clinical and Laboratory Research
https://www.readbyqxmd.com/read/28270440/liver-x-receptor-%C3%AE-induces-17%C3%AE-hydroxysteroid-dehydrogenase-13-expression-through-srebp-1c
#6
Wen Su, Jun Peng, Sha Li, Yu-Bing Dai, Chun-Jiong Wang, Hu Xu, Min Gao, Xiong-Zhong Ruan, Jan-Ake Gustafsson, Xiao-Yan Zhang, You-Fei Guan
Liver X receptors, including LXRα and LXRβ, are known to be master regulators of liver lipid metabolism. Activation of LXRα increases hepatic lipid storage in lipid droplets (LDs). 17β-hydroxysteroid dehydrogenase-13 (17β-HSD13), a recently identified liver-specific LD-associated protein, has been reported to be involved in the development of nonalcoholic fatty liver disease. However, little is known about its transcriptional regulation. In the present study, we aimed at determining whether 17β-HSD13 gene transcription is controlled by LXRs...
March 7, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28266648/the-trisaccharide-raffinose-modulates-epidermal-differentiation-through-activation-of-liver-x-receptor
#7
Tae-Young Na, Gyeong-Hwan Kim, Hyeon-Jeong Oh, Min-Ho Lee, Yong-Hyun Han, Ki Taek Kim, Ji-Su Kim, Dae-Duk Kim, Mi-Ock Lee
The epidermal barrier function requires optimal keratinocyte differentiation and epidermal lipid synthesis. Liver X receptor (LXR) α and β, are important transcriptional regulators of the epidermal gene expression. Here, we show that raffinose, a ubiquitously present trisaccharide in plants, activated the transcriptional activity of LXRα/β, which led to the induction of genes required for keratinocyte differentiation such as involucrin and filaggrin, and genes involved in lipid metabolism and transport including SCD1 and ABCA1 in both HaCaT and normal human epidermal keratinocytes...
March 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28259649/role-of-the-liver-x-receptors-in-skin-physiology-putative-pharmacological-targets-in-human-diseases
#8
REVIEW
Zangbéwendé Guy Ouedraogo, Allan Fouache, Amalia Trousson, Silvère Baron, Jean-Marc A Lobaccaro
Liver X receptors (LXRs) are members of the nuclear receptor superfamily that have been shown to regulate various physiological functions such as lipid metabolism and cholesterol homeostasis. Concordant reports have elicited the possibility to target them to cure many human diseases including arteriosclerosis, cancer, arthritis, and diabetes. The high relevance of modulating LXR activities to treat numerous skin diseases, mainly those with exacerbated inflammation processes, contrasts with the lack of approved therapeutic use...
March 1, 2017: Chemistry and Physics of Lipids
https://www.readbyqxmd.com/read/28258092/impaired-adipose-expansion-caused-by-liver-x-receptor-activation-is-associated-with-insulin-resistance-in-mice-fed-a-high-fat-diet
#9
Yueting Dong, Zhiye Xu, Ziyi Zhang, Xueyao Yin, Xihua Lin, Hong Li, Fenping Zheng
Liver X receptors (LXR) are deemed as potential drug targets for atherosclerosis, whereas a role in adipose tissue expansion and its relation to insulin sensitivity remains unclear. To assess the metabolic effects of LXR activation by the dual LXRα/β agonist T0901317, C57BL/6 mice fed a high-fat diet (HFD) were treated with T0901317 (30 mg/kg once daily by intraperitoneal injection) for 3 weeks. Differentiated 3T3-L1 adipocytes were used for analysing the effect of T0901317 on glucose uptake. The following results were obtained from this study...
April 2017: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/28257661/alisol-b-23-acetate-from-the-rhizomes-of-alisma-orientale-is-a-natural-agonist-of-the-human-pregnane-x-receptor
#10
Yuichiro Kanno, Tomofumi Yatsu, Naoya Yamashita, Shuai Zhao, Wei Li, Miyuki Imai, Manami Kashima, Yoshio Inouye, Kiyomitsu Nemoto, Kazuo Koike
BACKGROUND: Pregnane X receptor (PXR) is a key regulator of the induction of drug metabolizing enzymes. PXR has been studied for its importance in drug-drug or herb-drug interactions, and it is also a molecular target for the treatment of inflammatory and metabolic diseases. PURPOSE: This study aims to determine new natural PXR-ligands from traditional plant medicines. METHODS: The PXR activation activity was measured by a mammalian one hybrid assay of PXR...
March 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28244871/expression-of-srebp-1c-requires-srebp-2-mediated-generation-of-a-sterol-ligand-for-lxr-in-livers-of-mice
#11
Shunxing Rong, Víctor A Cortés, Shirya Rashid, Norma N Anderson, Jeffrey G McDonald, Guosheng Liang, Young-Ah Moon, Robert E Hammer, Jay D Horton
The synthesis of cholesterol and fatty acids (FA) in the liver is independently regulated by SREBP-2 and SREBP-1c, respectively. Here, we genetically deleted Srebf-2 from hepatocytes and confirmed that SREBP-2 regulates all genes involved in cholesterol biosynthesis, the LDL receptor, and PCSK9; a secreted protein that degrades LDL receptors in the liver. Surprisingly, we found that elimination of Srebf-2 in hepatocytes of mice also markedly reduced SREBP-1c and the expression of all genes involved in FA and triglyceride synthesis that are normally regulated by SREBP-1c...
February 28, 2017: ELife
https://www.readbyqxmd.com/read/28244008/liver-x-receptor-genes-variants-modulate-als-phenotype
#12
Kevin Mouzat, Nicolas Molinari, Jovana Kantar, Anne Polge, Philippe Corcia, Philippe Couratier, Pierre Clavelou, Raul Juntas-Morales, Nicolas Pageot, Jean -Marc A Lobaccaro, Cedric Raoul, Serge Lumbroso, William Camu
Amyotrophic lateral sclerosis (ALS) is one of the most severe motor neuron (MN) disorders in adults. Phenotype of ALS patients is highly variable and may be influenced by modulators of energy metabolism. Recent works have implicated the liver X receptors α and β (LXRs), either in the propagation process of ALS or in the maintenance of MN survival. LXRs are nuclear receptors activated by oxysterols, modulating cholesterol levels, a suspected modulator of ALS severity. In a cohort of 438 ALS patients and 330 healthy controls, the influence of LXR genes on ALS risk and phenotype was studied using single nucleotide polymorphisms (SNPs)...
February 27, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28241068/liver-x-receptor-agonist-treatment-significantly-affects-phenotype-and-transcriptome-of-apoe3-and-apoe4-abca1-haplo-deficient-mice
#13
Alexis Y Carter, Florent Letronne, Nicholas F Fitz, Anais Mounier, Cody M Wolfe, Kyong Nyon Nam, Valerie L Reeves, Hafsa Kamboh, Iliya Lefterov, Radosveta Koldamova
ATP-binding cassette transporter A1 (ABCA1) controls cholesterol and phospholipid efflux to lipid-poor apolipoprotein E (APOE) and is transcriptionally controlled by Liver X receptors (LXRs) and Retinoic X Receptors (RXRs). In APP transgenic mice, lack of Abca1 increased Aβ deposition and cognitive deficits. Abca1 haplo-deficiency in mice expressing human APOE isoforms, increased level of Aβ oligomers and worsened memory deficits, preferentially in APOE4 mice. In contrast upregulation of Abca1 by LXR/RXR agonists significantly ameliorated pathological phenotype of those mice...
2017: PloS One
https://www.readbyqxmd.com/read/28241052/osbpl10-rxra-and-lipid-metabolism-confer-african-ancestry-protection-against-dengue-haemorrhagic-fever-in-admixed-cubans
#14
Beatriz Sierra, Petr Triska, Pedro Soares, Gissel Garcia, Ana B Perez, Eglys Aguirre, Marisa Oliveira, Bruno Cavadas, Béatrice Regnault, Mayling Alvarez, Didye Ruiz, David C Samuels, Anavaj Sakuntabhai, Luisa Pereira, Maria G Guzman
Ethnic groups can display differential genetic susceptibility to infectious diseases. The arthropod-born viral dengue disease is one such disease, with empirical and limited genetic evidence showing that African ancestry may be protective against the haemorrhagic phenotype. Global ancestry analysis based on high-throughput genotyping in admixed populations can be used to test this hypothesis, while admixture mapping can map candidate protective genes. A Cuban dengue fever cohort was genotyped using a 2.5 million SNP chip...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28239648/liver-x-receptor-%C3%AE-mediates-hepatic-triglyceride-accumulation-through-upregulation-of-g0-g1-switch-gene-2-expression
#15
Bradlee L Heckmann, Xiaodong Zhang, Alicia M Saarinen, Gabriele Schoiswohl, Erin E Kershaw, Rudolf Zechner, Jun Liu
Liver X receptors (LXRs) are transcription factors essential for cholesterol homeostasis and lipogenesis. LXRα has been implicated in regulating hepatic triglyceride (TG) accumulation upon both influx of adipose-derived fatty acids (FAs) during fasting and stimulation of de novo FA synthesis by chemical agonism of LXR. However, whether or not a convergent mechanism is employed to drive deposition of FAs from these 2 different sources in TGs is undetermined. Here, we report that the G0/G1 Switch Gene 2 (G0S2), a selective inhibitor of intracellular TG hydrolysis/lipolysis, is a direct target gene of LXRα...
February 23, 2017: JCI Insight
https://www.readbyqxmd.com/read/28238905/seasonal-heat-stress-affects-adipose-tissue-proteome-toward-enrichment-of-the-nrf2-mediated-oxidative-stress-response-in-late-pregnant-dairy-cows
#16
M Zachut, G Kra, L Livshitz, Y Portnick, S Yakoby, G Friedlander, Y Levin
Environmental heat stress and metabolic stress during transition from late gestation to lactation are main factors limiting production in dairy cattle, and there is a complex interaction between them. Many proteins expressed in adipose tissue are involved in metabolic responses to stress. We aimed to investigate the effects of seasonal heat stress on adipose proteome in late-pregnant cows, and to identify biomarkers of heat stress. Late pregnant cows during summer heat stress (S, n=18), or during the winter season (W, n=12) were used...
February 24, 2017: Journal of Proteomics
https://www.readbyqxmd.com/read/28231341/identification-of-the-er-resident-e3-ubiquitin-ligase-rnf145-as-a-novel-lxr-regulated-gene
#17
Emma C L Cook, Jessica K Nelson, Vincenzo Sorrentino, Duco Koenis, Martina Moeton, Saskia Scheij, Roelof Ottenhoff, Boris Bleijlevens, Anke Loregger, Noam Zelcer
Cellular cholesterol metabolism is subject to tight regulation to maintain adequate levels of this central lipid molecule. Herein, the sterol-responsive Liver X Receptors (LXRs) play an important role owing to their ability to reduce cellular cholesterol load. In this context, identifying the full set of LXR-regulated genes will contribute to our understanding of their role in cholesterol metabolism. Using global transcriptional analysis we report here the identification of RNF145 as an LXR-regulated target gene...
2017: PloS One
https://www.readbyqxmd.com/read/28225186/randomised-clinical-trial-the-efficacy-and-safety-of-oltipraz-a-liver-x-receptor-alpha-inhibitory-dithiolethione-in-patients-with-non-alcoholic-fatty-liver-disease
#18
W Kim, B G Kim, J S Lee, C K Lee, J E Yeon, M S Chang, J H Kim, H Kim, S Yi, J Lee, J-Y Cho, S G Kim, J-H Lee, Y J Kim
BACKGROUND: Oltipraz is a synthetic dithiolethione with an antisteatotic effect by inhibiting the activity of liver X receptor alpha (LXR-α). Recent studies demonstrated the disruptive role of oltipraz on LXR-α-dependent lipogenesis in hepatocytes and a high-fat diet mouse model. AIM: To evaluate the efficacy and safety of oltipraz for reducing liver fat in subjects with non-alcoholic fatty liver disease (NAFLD). METHODS: We performed a multicentre, double-blind, placebo-controlled, phase II study...
February 22, 2017: Alimentary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28197211/therapeutic-effects-of-fermented-flax-seed-oil-on-nc-nga-mice-with-atopic-dermatitis-like-skin-lesions
#19
Joonhyoung Yang, Sangyeon Min, Seungug Hong
Background. Atopic Dermatitis (AD) is one of the most common chronic inflammatory skin diseases. Objective. This experiment aimed to study the effects of Fermented Flax Seed Oil (FFSO) on symptoms such as redness, eczema, and pruritus induced by AD. Materials and Methods. AD-induced NC/Nga mice were used to observe the immunological and therapeutic effects of FFSO on skin in vivo. Raw 264.7 cells were used to investigate the effects of FFSO in cells. Fc receptor expression and concentration of beta-hexosaminidase were measured...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/28169169/drugbank-screening-revealed-alitretinoin-and-bexarotene-as-liver-x-receptor-modulators
#20
Pascal Heitel, Janosch Achenbach, Daniel Moser, Ewgenij Proschak, Daniel Merk
In silico screening of DrugBank database to detect liver X receptor (LXR) agonism of marketed drugs using a self-organizing map and successive LXR-Gal4 hybrid reporter gene assay evaluation in vitro discovered alitretinoin and bexarotene as partial liver X receptor agonists. Dose-response curves demonstrated that plasma concentrations observed in clinical trials are sufficient for LXR activation and thus could account for LXR-mediated side-effects such as hypercholesterolemia and hyperlipidemia. The discovered drugs are the first reported dual LXR/RXR agonists and can serve as lead structures for LXR and dual LXR/RXR modulator development...
January 25, 2017: Bioorganic & Medicinal Chemistry Letters
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