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Natural products as modulators of the nuclear receptors and metabolic sensors LXR,FXR and RXR

Authors:	Verena Hiebl Angela Ladurner Simone Latkolik Verena M Dirsch

Institution:	University of Vienna, Department of Pharmacognosy, Althanstrasse 14, 1090 Vienna, Austria

Abstract:	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.

Keywords:	Natural products Nuclear receptors Liver X receptor Farnesoid X receptor Retinoid X receptor Metabolic syndrome Precision medicine 6-ECDCA 6α-ethyl-chenodeoxycholic acid (obeticholic acid) AA arachidonic acid ABC ATP-binding cassette transporter ACC acyl-CoA carboxylase AD Alzheimer's disease AF activation function ALS amyotrophic lateral sclerosis ALT alanine transaminase AMPK AMP-activated protein kinase ANGPTL-4 angiopoietin-like protein 4 AP-1 activator protein 1 aP2 adipocyte fatty acid-binding protein-2 APO apolipoprotein AR androgen receptor ARL7 ADP-ribosylation factor-like 7 ASBT apical sodium-dependent bile acid transporter BAAT bile acid CoA amino acid N-acetyltransferase BACS bile acid CoA synthase BGP Brazilian green propolis BSEP bile salt export pump CA cholic acid CAR constitutive androstane receptor CAT chloramphenicol acetyltransferase CD circular dichroism CD36 scavenger receptor class B member 3 CDCA chenodeoxycholic acid CETP cholesteryl ester transfer protein COX-2 cyclooxygenase 2 CPT1A carnitine palmitoyltransferase 1A CRBPII cellular retinol binding protein II CREB cAMP response element-binding protein CRHF CYP cytochrome P450 D9k calbindin D9k DBD DNA-binding domain DCA deoxycholic acid DHA docosahexaenoic acid DR direct repeat EERP ethanolic extracts of Brazilian red propolis EGCG Epigallocatechin-3-gallate ELOVL6 fatty acid elongase 6 ER estrogen receptor ERK1/2 extracellular signal-regulated protein kinase 1/2 ETB ethyl 2 4 6-trihydroxybenzoate FABP3 fatty acid binding protein 3 FAS fatty acid synthase FCHL familial combined hyperlipidemia FGF fibroblast growth factor FGFR4 fibroblast growth factor receptor 4 FXR farnesoid X receptor G6Pase glucose-6-phophatase GLUT4 glucose transporter 4 GR glucocorticoid receptor HDL high density lipoprotein HMGR HMG-CoA reductase HMOX-1 heme oxygenase-1 HNF4α hepatocyte nuclear factor 4 α HPLC-ESI-MS high-performance liquid chromatography-electrospray ionization mass spectrometry HSP27 heat shock protein 27 HTS high-throughput screening IBABP ileal bile acid binding-protein IBD inflammatory bowel disease ICP intrahepatic cholestasis of pregnancy IL-6 interleukin 6 iNOS inducible nitric oxide synthase IR inverted repeat ITC isothermal titration calorimetry JNK1/2 c-Jun N-terminal kinase 1/2 LBD ligand-binding domain LCA lithocholic acid LDL low density lipoprotein LDLR LDL receptor LPL lipoprotein lipase LRH-1 liver receptor homolog-1 LXR liver X receptor MDR3 multidrug resistance protein 3 MR mineralocorticoid receptor MRP2/4 multidrug resistance-associated protein 2/4 MS multiple sclerosis Mylip/Idol inducible degrader of the LDL receptor NAFLD nonalcoholic fatty liver disease NF-κB nuclear factor κB NMR nuclear magnetic resonance NPC1L1 Niemann-Pick C1-like protein 1 NR nuclear receptor NTCP sodium taurocholate cotransporting polypeptide Nur77 nuclear receptor subfamily 4 group A member 1 (nerve growth factor induced gene B) Nurr1 nuclear receptor subfamily 4 group A member 2 (Nur-related factor-1) OA oleic acid OATP organic anion transporting polypeptide OSTα/β organic solute transporter α/β PBC primary biliary cirrhosis PEPCK phosphoenolpyruvate carboxykinase PLTP phospholipid transfer protein PPAR peroxisome proliferator-activated receptor PR progesterone receptor PUFAs polyunsaturated fatty acids PXR pregnane X receptor Q3GA RA retinoic acid RAR retinoic acid receptor RC Riccardin C RCT reverse cholesterol transport RE response element RF Riccardin F ROR RAR-related orphan receptor RVS RXR retinoid X receptor SBARM selective bile acid receptor modulator SCD-1 stearoyl-CoA desaturase-1 SHP small heterodimer partner SNP single nucleotide polymorphism SNuRMs selective NR modulators SOAE aqueous extract of sesame oil SPR surface plasmon resonance SR-A scavenger receptor class A SR-BI scavenger receptor class B type I SRC-1/2/3 steroid receptor coactivator-1/2/3 SREBP-1c sterol regulatory element binding protein-1c SRXRMs selective RXR modulators SULT2A1 sulfotransferase 2A1 SUMO small ubiquitin-like modifier TG triglyceride TICE transintestinal cholesterol efflux TLR Toll-like receptor TR thyroid hormone receptor TR-FRET time-resolved fluorescence resonance energy transfer TRPV6 transient receptor potential vanilloid 6 UC ulcerative colitis UGT2B4 UDP-glucuronosyltransferase family 2 member B4 VDR vitamin D receptor VLDL very low density lipoprotein WBM white button mushroom WHO World Health Organization
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