LPS/IL-1 Mediated Inhibition of RXR Function
Endotoxin lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, potently stimulates host innate immune response. LPS binds the CD14/TRL4/MD2 receptor complex, which promotes the secretion of pro-inflammatory cytokines (IL-1, TNFα) in different cell types, but especially in macrophages. Infection, inflammation and injury down-regulate the expression of hepatic genes involved in a variety of physiological processes, collectively known as the negative hepatic acute phase response (APR). Many of the repressed genes during APR are regulated by the nuclear hormone receptor retinoid X receptor α (RXRα). The retinoid X receptors (RXRs) are nuclear receptors that mediate the biological effects of retinoids by their involvement in retinoic acid-mediated gene activation...
Pathway Summary
Endotoxin lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, potently stimulates host innate immune response. LPS binds the CD14/TRL4/MD2 receptor complex, which promotes the secretion of pro-inflammatory cytokines (IL-1, TNFα) in different cell types, but especially in macrophages. Infection, inflammation and injury down-regulate the expression of hepatic genes involved in a variety of physiological processes, collectively known as the negative hepatic acute phase response (APR). Many of the repressed genes during APR are regulated by the nuclear hormone receptor retinoid X receptor α (RXRα). The retinoid X receptors (RXRs) are nuclear receptors that mediate the biological effects of retinoids by their involvement in retinoic acid-mediated gene activation. RXRα represents the dimerization partner for the type II nuclear receptors. This group includes the liver X receptor (LXR), farnesoid X receptor (FXR), retinoic acid receptor (RAR), constitutive androstane receptor (CAR), pregnane X receptor (PXR) and peroxisome proliferator-activated receptor (PPAR). In response to pro-inflammatory cytokines signaling, RXRα undergoes a JNK-mediated, CRM-1-dependent nuclear export, leading to decreased nuclear RXRα levels and reduced nuclear DNA binding and transcriptional activity. Reduction in the expression of hepatic transport proteins (ABC, OATP, MDR1, NTCP), metabolizing enzymes (CYP, GST, UGT, SOD) and biosynthesis enzymes (CYP7A1) leads to impaired metabolism, transport and/or biosynthesis of lipid, cholesterol, bile acid and xenobiotics.
LPS/IL-1 Mediated Inhibition of RXR Function Genes list
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ABCA1ATP binding cassette subfamily A member 1 ABCB1ATP binding cassette subfamily B member 1 ABCB11ATP binding cassette subfamily B member 11 ABCB9ATP binding cassette subfamily B member 9 ABCC2ATP binding cassette subfamily C member 2 ABCC3ATP binding cassette subfamily C member 3 ABCC4ATP binding cassette subfamily C member 4 ABCG1ATP binding cassette subfamily G member 1 ABCG5ATP binding cassette subfamily G member 5 ABCG8ATP binding cassette subfamily G member 8 ACOX1acyl-CoA oxidase 1 ACOX2acyl-CoA oxidase 2 ACOX3acyl-CoA oxidase 3, pristanoyl ACSBG1acyl-CoA synthetase bubblegum family member 1 ACSBG2acyl-CoA synthetase bubblegum family member 2 ACSF2acyl-CoA synthetase family member 2 ACSL1acyl-CoA synthetase long chain family member 1 ACSL3acyl-CoA synthetase long chain family member 3 ACSL4acyl-CoA synthetase long chain family member 4 ACSL5acyl-CoA synthetase long chain family member 5 ACSL6acyl-CoA synthetase long chain family member 6 ACSM1acyl-CoA synthetase medium chain family member 1 ALAS15'-aminolevulinate synthase 1 ALDH16A1aldehyde dehydrogenase 16 family member A1 ALDH18A1aldehyde dehydrogenase 18 family member A1 ALDH1A1aldehyde dehydrogenase 1 family member A1 ALDH1A2aldehyde dehydrogenase 1 family member A2 ALDH1A3aldehyde dehydrogenase 1 family member A3 ALDH1B1aldehyde dehydrogenase 1 family member B1 ALDH1L1aldehyde dehydrogenase 1 family member L1 ALDH1L2aldehyde dehydrogenase 1 family member L2 ALDH2aldehyde dehydrogenase 2 family member ALDH3A1aldehyde dehydrogenase 3 family member A1 ALDH3A2aldehyde dehydrogenase 3 family member A2 ALDH3B1aldehyde dehydrogenase 3 family member B1 ALDH3B2aldehyde dehydrogenase 3 family member B2 ALDH4A1aldehyde dehydrogenase 4 family member A1 ALDH5A1aldehyde dehydrogenase 5 family member A1 ALDH6A1aldehyde dehydrogenase 6 family member A1 ALDH7A1aldehyde dehydrogenase 7 family member A1 ALDH8A1aldehyde dehydrogenase 8 family member A1 ALDH9A1aldehyde dehydrogenase 9 family member A1 APOC1apolipoprotein C1 APOC2apolipoprotein C2 APOC4apolipoprotein C4 APOEapolipoprotein E CATcatalase CD14CD14 molecule CES2carboxylesterase 2 CETPcholesteryl ester transfer protein CHST1carbohydrate sulfotransferase 1 CHST10carbohydrate sulfotransferase 10 CHST11carbohydrate sulfotransferase 11 CHST12carbohydrate sulfotransferase 12 CHST13carbohydrate sulfotransferase 13 CHST15carbohydrate sulfotransferase 15 CHST2carbohydrate sulfotransferase 2 CHST3carbohydrate sulfotransferase 3 CHST4carbohydrate sulfotransferase 4 CHST5carbohydrate sulfotransferase 5 CHST7carbohydrate sulfotransferase 7 CPT1Acarnitine palmitoyltransferase 1A CPT1Bcarnitine palmitoyltransferase 1B CPT1Ccarnitine palmitoyltransferase 1C CPT2carnitine palmitoyltransferase 2 CRATcarnitine O-acetyltransferase CYP2B6cytochrome P450 family 2 subfamily B member 6 CYP2C18cytochrome P450 family 2 subfamily C member 18 CYP2C19cytochrome P450 family 2 subfamily C member 19 CYP2C8cytochrome P450 family 2 subfamily C member 8 CYP2C9cytochrome P450 family 2 subfamily C member 9 CYP2D6cytochrome P450 family 2 subfamily D member 6 CYP2E1cytochrome P450 family 2 subfamily E member 1 CYP2F1cytochrome P450 family 2 subfamily F member 1 CYP2J2cytochrome P450 family 2 subfamily J member 2 CYP2R1cytochrome P450 family 2 subfamily R member 1 CYP2S1cytochrome P450 family 2 subfamily S member 1 CYP2U1cytochrome P450 family 2 subfamily U member 1 CYP3A4cytochrome P450 family 3 subfamily A member 4 CYP3A5cytochrome P450 family 3 subfamily A member 5 CYP3A7cytochrome P450 family 3 subfamily A member 7 CYP7A1cytochrome P450 family 7 subfamily A member 1 ECSITECSIT signaling integrator FABP1fatty acid binding protein 1 FABP2fatty acid binding protein 2 FABP3fatty acid binding protein 3 FABP4fatty acid binding protein 4 FABP5fatty acid binding protein 5 FABP6fatty acid binding protein 6 FABP7fatty acid binding protein 7 FABP9fatty acid binding protein 9 FMO1flavin containing dimethylaniline monoxygenase 1 FMO2flavin containing dimethylaniline monoxygenase 2 FMO3flavin containing dimethylaniline monoxygenase 3 FMO4flavin containing dimethylaniline monoxygenase 4 FMO5flavin containing dimethylaniline monoxygenase 5 GAL3ST2galactose-3-O-sulfotransferase 2 GSTA1glutathione S-transferase alpha 1 GSTA2glutathione S-transferase alpha 2 GSTA3glutathione S-transferase alpha 3 GSTA4glutathione S-transferase alpha 4 GSTA5glutathione S-transferase alpha 5 GSTK1glutathione S-transferase kappa 1 GSTM1glutathione S-transferase mu 1 GSTM2glutathione S-transferase mu 2 GSTM3glutathione S-transferase mu 3 GSTM4glutathione S-transferase mu 4 GSTM5glutathione S-transferase mu 5 GSTO1glutathione S-transferase omega 1 GSTO2glutathione S-transferase omega 2 GSTP1glutathione S-transferase pi 1 GSTT1glutathione S-transferase theta 1 GSTZ1glutathione S-transferase zeta 1 HMGCS13-hydroxy-3-methylglutaryl-CoA synthase 1 HMGCS23-hydroxy-3-methylglutaryl-CoA synthase 2 HS2ST1heparan sulfate 2-O-sulfotransferase 1 HS3ST1heparan sulfate-glucosamine 3-sulfotransferase 1 HS3ST2heparan sulfate-glucosamine 3-sulfotransferase 2 HS3ST3A1heparan sulfate-glucosamine 3-sulfotransferase 3A1 HS3ST3B1heparan sulfate-glucosamine 3-sulfotransferase 3B1 HS3ST4heparan sulfate-glucosamine 3-sulfotransferase 4 HS3ST5heparan sulfate-glucosamine 3-sulfotransferase 5 HS3ST6heparan sulfate-glucosamine 3-sulfotransferase 6 HS6ST1heparan sulfate 6-O-sulfotransferase 1 HS6ST2heparan sulfate 6-O-sulfotransferase 2 HS6ST3heparan sulfate 6-O-sulfotransferase 3 IL18interleukin 18 IL18RAPinterleukin 18 receptor accessory protein IL1Ainterleukin 1 alpha IL1Binterleukin 1 beta IL1F10interleukin 1 family member 10 IL1R1interleukin 1 receptor type 1 IL1R2interleukin 1 receptor type 2 IL1RAPinterleukin 1 receptor accessory protein IL1RAPL1interleukin 1 receptor accessory protein like 1 IL1RAPL2interleukin 1 receptor accessory protein like 2 IL1RL1interleukin 1 receptor like 1 IL1RL2interleukin 1 receptor like 2 IL1RNinterleukin 1 receptor antagonist IL33interleukin 33 IL36Ainterleukin 36 alpha IL36Binterleukin 36 beta IL36Ginterleukin 36 gamma IL36RNinterleukin 36 receptor antagonist IL37interleukin 37 IL4I1interleukin 4 induced 1 IRAK1interleukin 1 receptor associated kinase 1 JUNJun proto-oncogene, AP-1 transcription factor subunit LBPlipopolysaccharide binding protein LIPClipase C, hepatic type LY96lymphocyte antigen 96 MAOAmonoamine oxidase A MAOBmonoamine oxidase B MAP2K4mitogen-activated protein kinase kinase 4 MAP2K7mitogen-activated protein kinase kinase 7 MAP3K1mitogen-activated protein kinase kinase kinase 1 MAP3K7mitogen-activated protein kinase kinase kinase 7 MAPK8mitogen-activated protein kinase 8 MAPK9mitogen-activated protein kinase 9 MGMTO-6-methylguanine-DNA methyltransferase MGST1microsomal glutathione S-transferase 1 MGST2microsomal glutathione S-transferase 2 MGST3microsomal glutathione S-transferase 3 MYD88MYD88 innate immune signal transduction adaptor NCOA1nuclear receptor coactivator 1 NDST1N-deacetylase and N-sulfotransferase 1 NDST2N-deacetylase and N-sulfotransferase 2 NDST3N-deacetylase and N-sulfotransferase 3 NDST4N-deacetylase and N-sulfotransferase 4 NGFRnerve growth factor receptor NR0B2nuclear receptor subfamily 0 group B member 2 NR1H2nuclear receptor subfamily 1 group H member 2 NR1H3nuclear receptor subfamily 1 group H member 3 NR1H4nuclear receptor subfamily 1 group H member 4 NR1I2nuclear receptor subfamily 1 group I member 2 NR1I3nuclear receptor subfamily 1 group I member 3 NR5A2nuclear receptor subfamily 5 group A member 2 PAPSS23'-phosphoadenosine 5'-phosphosulfate synthase 2 PLTPphospholipid transfer protein PPARAperoxisome proliferator activated receptor alpha PPARGC1APPARG coactivator 1 alpha PPARGC1BPPARG coactivator 1 beta RARAretinoic acid receptor alpha RXRAretinoid X receptor alpha SCARB1scavenger receptor class B member 1 SLC10A1solute carrier family 10 member 1 SLC27A1solute carrier family 27 member 1 SLC27A2solute carrier family 27 member 2 SLC27A3solute carrier family 27 member 3 SLC27A4solute carrier family 27 member 4 SLC27A5solute carrier family 27 member 5 SLC27A6solute carrier family 27 member 6 SLC35A2solute carrier family 35 member A2 SLCO1A2solute carrier organic anion transporter family member 1A2 SLCO1B3solute carrier organic anion transporter family member 1B3 SMOXspermine oxidase SOD3superoxide dismutase 3 SREBF1sterol regulatory element binding transcription factor 1 SULT1A1sulfotransferase family 1A member 1 SULT1A2sulfotransferase family 1A member 2 SULT1B1sulfotransferase family 1B member 1 SULT1C2sulfotransferase family 1C member 2 SULT1C3sulfotransferase family 1C member 3 SULT1C4sulfotransferase family 1C member 4 SULT1E1sulfotransferase family 1E member 1 SULT2A1sulfotransferase family 2A member 1 SULT2B1sulfotransferase family 2B member 1 SULT4A1sulfotransferase family 4A member 1 TLR4toll like receptor 4 TNFtumor necrosis factor TNFRSF11BTNF receptor superfamily member 11b TNFRSF1ATNF receptor superfamily member 1A TNFRSF1BTNF receptor superfamily member 1B TRAF2TNF receptor associated factor 2 TRAF6TNF receptor associated factor 6 USTuronyl 2-sulfotransferase XPO1exportin 1
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