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Jianjia Fan, Rui Qi Zhao, Cameron Parro, Wenchen Zhao, Hsien-Ya Chou, Jerome Robert, Tarek Z Deeb, Carina Raynoschek, Samantha Barichievy, Ola Engvist, Marcello Maresca, Ryan Hicks, Johan Meuller, Stephen J Moss, Nicholas J Brandon, Michael W Wood, Iva Kulic, Cheryl L Wellington
Apolipoprotein E (apoE) is the primary lipid carrier within the central nervous system (CNS) and the strongest genetic risk factor for late onset Alzheimer's disease (AD). ApoE is primarily lipidated via the ATP-binding cassette transporter 1 (ABCA1), and both are under transcriptional regulation by the liver X nuclear receptor (LXR). Considerable evidence from genetic (using ABCA1 overexpression) and pharmacological (using synthetic LXR agonists) studies in AD mouse models suggests that increased levels of lipidated apoE can improve cognitive performance and, in some strains, can reduce amyloid burden...
March 21, 2018: Journal of Lipid Research
Verena Hiebl, Angela Ladurner, Simone Latkolik, Verena M Dirsch
Nuclear receptors (NRs) represent attractive targets for the treatment of metabolic syndrome-related diseases. In addition, natural products are an interesting pool of potential ligands since they have been refined under evolutionary pressure to interact with proteins or other biological targets. This review aims to briefly summarize current basic knowledge regarding the liver X (LXR) and farnesoid X receptors (FXR) that form permissive heterodimers with retinoid X receptors (RXR). Natural product-based ligands for these receptors are summarized and the potential of LXR, FXR and RXR as targets in precision medicine is discussed...
March 13, 2018: Biotechnology Advances
Dicson Sheeja Malar, Venkatesan Suryanarayanan, Mani Iyer Prasanth, Sanjeev Kumar Singh, Krishnaswamy Balamurugan, Kasi Pandima Devi
Amyloid beta (Aβ) formation is one of the neuropathological hallmarks of Alzheimer's disease (AD), which induces the generation of reactive oxygen species (ROS), further leading to the alteration of several signalling pathways. In the present study, vitexin has been evaluated for its neuroprotective activity against Aβ25-35 induced toxicity in Neuro-2a cells. Results of cell free studies indicated that vitexin significantly inhibited the aggregation of Aβ25-35 . Studies in Neuro-2a cells revealed that Aβ25-35 significantly affected the cell viability by inducing ROS mediated toxicity and apoptosis...
March 12, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Carrie J Finno, Matthew H Bordbari, Giuliana Gianino, Brittni Ming-Whitfield, Erin Burns, Janel Merkel, Monica Britton, Blythe Durbin-Johnson, Erica A Sloma, Marissa McMackin, Gino Cortopassi, Victor Rivas, Marietta Barro, Cecilia K Tran, Ingrid Gennity, Hadi Habib, Libin Xu, Birgit Puschner, Andrew D Miller
Mice with deficiency in tocopherol (alpha) transfer protein gene develop peripheral tocopherol deficiency and sensory neurodegeneration. Ttpa-/- mice maintained on diets with deficient α-tocopherol (α-TOH) had proprioceptive deficits by six months of age, axonal degeneration and neuronal chromatolysis within the dorsal column of the spinal cord and its projections into the medulla. Transmission electron microscopy revealed degeneration of dorsal column axons. We addressed the potential pathomechanism of α-TOH deficient neurodegeneration by global transcriptome sequencing within the spinal cord and cerebellum...
March 8, 2018: Free Radical Biology & Medicine
Shuyuan Guo, Luxiao Li, Huiyong Yin
Cholesterol is an important lipid for maintaining cellular membrane fluidity and generation of various hormones and bile acids. Thus it is critical to maintain cholesterol homeostasis including absorption, trafficking, biosynthesis, and efflux; dysregulation of cholesterol homeostasis may lead to human disorders such as atherosclerosis. As a cholesterol sensor, nuclear receptor liver X receptor (LXR) is an important factor regulating cholesterol homeostasis. Extensive research has been carried out to examine the roles of LXR in atherosclerosis...
March 1, 2018: Cardiovascular & Hematological Disorders Drug Targets
Susana Beceiro, Attila Pap, Zsolt Czimmerer, Tamer Sallam, Jose A Guillén, Germán Gallardo, Cynthia Hong, Noelia A-Gonzalez, Carlos Tabraue, Mercedes Diaz, Felix Lopez, Jonathan Matalonga, Annabel F Valledor, Pilar Dominguez, Carlos Ardavin, Cristina Delgado-Martin, Santiago Partida-Sanchez, Jose Luis Rodriguez-Fernandez, Laszlo Nagy, Peter Tontonoz, Antonio Castrillo
The liver X receptors (LXRs) are ligand-activated nuclear receptors with established roles in the maintenance of lipid homeostasis in multiple tissues. LXRs exert additional biological functions as negative regulators of inflammation, particularly in macrophages. However, the transcriptional responses controlled by LXRs in other myeloid cells, such as dendritic cells (DC), are still poorly understood. Here we used gain- and loss-of-function models to characterize the impact of LXR deficiency on DC activation programs...
March 5, 2018: Molecular and Cellular Biology
Holly Whitton, Larry N Singh, Marissa A Patrick, Andrew J Price, Fernando G Osorio, Carlos López-Otín, Irina M Bochkis
Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age-dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina-associated domains (LADs) using lamin B1 ChIP-Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1-associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors...
February 27, 2018: Aging Cell
Sang Bong Ahn, Dae Won Jun, Kiseok Jang, Byung Hoon Lee, Kye Jung Shin
Background/Aims: Intestinal cholesterol absorption includes intestinal Niemann-Pick C1-like 1 (NPC1L1) and is an important target pathway in nonalcoholic fatty liver disease (NAFLD). We investigated the expression of NPC1L1 and its correlation with liver X receptor (LXR) expression in peripheral mononuclear (PMN) cells in patients with NAFLD. Methods: We evaluated intestinal expression of NPC1L1 in 25 NAFLD patients and 28 healthy controls. We calculated the mRNA expression levels of LXR and farnesoid X receptor (FXR), which are master players of cholesterol metabolism in PMN cells...
February 23, 2018: Korean Journal of Internal Medicine
Shuhong Han, Haoyang Zhuang, Stepan Shumyak, Jingfan Wu, Chao Xie, Hui Li, Li-Jun Yang, Westley H Reeves
The generation of CD138+ phagocytic macrophages with an alternative (M2) phenotype that clear apoptotic cells from tissues is defective in lupus. Liver X receptor-alpha (LXRα) is an oxysterol-regulated transcription factor that promotes reverse cholesterol transport and alternative (M2) macrophage activation. Conversely, hypoxia-inducible factor 1-α (HIF1α) promotes classical (M1) macrophage activation. The objective of this study was to see if lupus can be treated by enhancing the generation of M2-like macrophages using LXR agonists...
2018: Frontiers in Immunology
Daisuke Aibara, Kimihiko Matsusue, Soichi Takiguchi, Frank J Gonzalez, Shigeru Yamano
Fat-specific protein 27 (FSP27) is highly expressed in the fatty liver of genetically obese ob/ob mice and promotes hepatic triglyceride (TG) accumulation. The nuclear hormone receptor liver X receptor α (LXRα) also plays a critical role in the control of TG levels in the liver. The present study demonstrated transcriptional regulation of Fsp27a and Fsp27b genes by LXRα. Treatment with the LXR ligand T0901317 markedly increased Fsp27a and Fsp27b mRNAs in wild-type C57BL/6J and ob/ob mouse livers. A reporter assay indicated that two LXR-responsive elements (LXREs) are necessary for LXRα-dependent induction of Fsp27a and Fsp27b promoter activities...
February 15, 2018: Molecular and Cellular Endocrinology
Xin Wang, Kaimin Lu, Hao Luo, Danfeng Liang, Xin Long, Yuan Yuan, Chuanfang Wu, Jinku Bao
Liver X receptor (LXR), a member of the nuclear receptor superfamily, mainly serves as a reverse cholesterol transporter in lipid metabolism. It has been demonstrated that LXR is a promising target for the treatment of cardiovascular diseases. LXR is also involved in cancer metabolism, glucose homeostasis, immunity, and various physiological processes. The antitumor function of LXR has become of great interest to researchers in recent years. However, while it is believed that activating LXR with small molecules could be a promising approach to cancer treatment, effective drugs that target LXR are yet to be reported...
February 15, 2018: Journal of Molecular Modeling
Anthony Mukwaya, Anton Lennikov, Maria Xeroudaki, Pierfrancesco Mirabelli, Mieszko Lachota, Lasse Jensen, Beatrice Peebo, Neil Lagali
Inflammation in the normally immune-privileged cornea can initiate a pathologic angiogenic response causing vision-threatening corneal neovascularization. Inflammatory pathways, however, are numerous, complex and are activated in a time-dependent manner. Effective resolution of inflammation and associated angiogenesis in the cornea requires knowledge of these pathways and their time dependence, which has, to date, remained largely unexplored. Here, using a model of endogenous resolution of inflammation-induced corneal angiogenesis, we investigate the time dependence of inflammatory genes in effecting capillary regression and the return of corneal transparency...
February 14, 2018: Angiogenesis
Vladimir S Shavva, Denis A Mogilenko, Ekaterina V Nekrasova, Andrey S Trulioff, Igor V Kudriavtsev, Ekaterina E Larionova, Anna V Babina, Ella B Dizhe, Boris V Missyul, Sergey V Orlov
Apolipoprotein A-I (ApoA-I) is the main structural and functional protein component of high-density lipoprotein. ApoA-I has been shown to regulate lipid metabolism and inflammation in macrophages. Recently, we found the moderate expression of endogenous apoA-I in human monocytes and macrophages and showed that pro-inflammatory cytokine tumor necrosis factor α (TNFα) increases apoA-I mRNA and stimulates ApoA-I protein secretion by human monocytes and macrophages. Here, we present data about molecular mechanisms responsible for the TNFα-mediated activation of apoA-I gene in human monocytes and macrophages...
February 13, 2018: Molecular and Cellular Biochemistry
Tamer Sallam, Marius Jones, Brandon J Thomas, Xiaohui Wu, Thomas Gilliland, Kevin Qian, Ascia Eskin, David Casero, Zhengyi Zhang, Jaspreet Sandhu, David Salisbury, Prashant Rajbhandari, Mete Civelek, Cynthia Hong, Ayaka Ito, Xin Liu, Bence Daniel, Aldons J Lusis, Julian Whitelegge, Laszlo Nagy, Antonio Castrillo, Stephen Smale, Peter Tontonoz
Nuclear receptors regulate gene expression in response to environmental cues, but the molecular events governing the cell type specificity of nuclear receptors remain poorly understood. Here we outline a role for a long noncoding RNA (lncRNA) in modulating the cell type-specific actions of liver X receptors (LXRs), sterol-activated nuclear receptors that regulate the expression of genes involved in cholesterol homeostasis and that have been causally linked to the pathogenesis of atherosclerosis. We identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the gene Abca1, which is critical for regulation of cholesterol efflux...
March 2018: Nature Medicine
Mario D Martínez, Alberto A Ghini, M Virginia Dansey, Adriana S Veleiro, Adali Pecci, Lautaro D Alvarez, Gerardo Burton
The Liver X receptors (LXRs) are members of the nuclear receptor family, that play fundamental roles in cholesterol transport, lipid metabolism and modulation of inflammatory responses. In recent years, the synthetic steroid N,N-dimethyl-3β-hydroxycholenamide (DMHCA) arised as a promising LXR ligand. This compound was able to dissociate certain beneficial LXRs effects from those undesirable ones involved in triglyceride metabolism. Here, we synthetized a series of DMHCA analogues with different modifications in the steroidal nucleus involving the A/B ring fusion, that generate changes in the overall conformation of the steroid...
January 31, 2018: Bioorganic & Medicinal Chemistry
Cristina Otero-Rodiño, Ana Rocha, Rosa Álvarez-Otero, Rosa M Ceinos, Marcos A López-Patiño, Jesús M Míguez, José Miguel Cerdá-Reverter, José L Soengas
To assess the hypothesis of glucosensing systems present in fish telencephalon, we first demonstrated in rainbow trout by in situ hybridization the presence of glucokinase (GK). Then, we assessed the response of glucosensing markers in rainbow trout telencephalon 6h after ICV treatment with glucose or 2-deoxyglucose (inducing glucoprivation). We evaluated the response of parameters related to the mechanisms dependent on GK, liver X receptor (LXR), mitochondrial activity, sweet taste receptor, and sodium-glucose linked transporter 1 (SGLT-1)...
February 10, 2018: Journal of Neuroendocrinology
Gregorio Peron, Davide Santarossa, Dario Voinovich, Stefano Dall'Acqua, Stefania Sut
BACKGROUND AND OBJECTIVE: Green coffee bean extract is used as herbal medicine or supplement for weight reduction and obesity. The active constituents are considered caffeine and chlorogenic acid (CGA) derivatives. The mode of action of CGA is still unclear and can be related to peroxisome proliferator-activated receptor α (PPAR-α) and liver X receptor Rα (LXR-α). Metabolomics may be an innovative tool for the description and discovery of the multiple target nature of such phytocomplex...
January 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Oumei Cheng, Xiaoyan Tian, Ying Luo, Shaoshan Mai, Yang Yang, Shengnan Kuang, Qi Chen, Jie Ma, Beibei Chen, Rong Li, Lu Yang, Huan Li, Congli Hu, Jiahua Zhang, Zhihao Chen, Yuke Li, Hui Xia, Ying Xu, Junqing Yang
Dopaminergic (DA) neurons derived from bone marrow derived mesenchymal stem cells (BMSCs) maybe a valuable source for cell replacement therapy in Parkinson disease. Recent studies showed that new functions of LXR and their ligands have been proposed to prevent PD in the adult nervous system. The present study was designed to observe the effect of liver X receptors (LXR) agonist on differentiation of rat BMSCs into DA neurons. Expressions of the neuronal markers (Tuj1 and Nestin), the specific marker of DA neurons (tyrosine hydroxylase, TH), LXR α and LXR β were measured by immunocytochemical assay and TH/Tuj1 positive cells were determined by quantitative cell count analyses...
January 2, 2018: Oncotarget
Mehdi Hichor, Venkat Krishnan Sundaram, Stéphanie A Eid, Ronza Abdel-Rassoul, Patrice X Petit, Didier Borderie, Jean Bastin, Assaad A Eid, Marin Manuel, Julien Grenier, Charbel Massaad
Reactive oxygen species (ROS) modify proteins and lipids leading to deleterious outcomes. Thus, maintaining their homeostatic levels is vital. This study highlights the endogenous role of LXRs (LXRα and β) in the regulation of oxidative stress in peripheral nerves. We report that the genetic ablation of both LXR isoforms in mice (LXRdKO) provokes significant locomotor defects correlated with enhanced anion superoxide production, lipid oxidization and protein carbonylation in the sciatic nerves despite the activation of Nrf2-dependant antioxidant response...
February 6, 2018: Scientific Reports
Marc Poirot, Sandrine Silvente-Poirot
Dendrogenin A (DDA) is a mammalian cholesterol metabolite recently identified that displays tumor suppressor properties. The discovery of DDA has revealed the existence in mammals of a new metabolic branch in the cholesterol pathway centered on 5,6α-epoxycholesterol and bridging cholesterol metabolism with histamine metabolism. Metabolic studies showed a drop in DDA levels in cancer cells and tumors compared to normal cells, suggesting a link between DDA metabolism deregulation and oncogenesis. Importantly, complementation of cancer cells with DDA induced 1) cancer cell re-differentiation, 2) blockade of 6-oxo-cholestan-3β,5α-diol (OCDO) production, an endogenous tumor promoter and 3) lethal autophagy in tumors...
February 1, 2018: Biochemical Pharmacology
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