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Understanding the physiological functions of the host xenobiotic-sensing nuclear receptors PXR and CAR on the gut microbiome using genetically modified mice

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Acta Pharmaceutica Sinica B 2022年第2期12卷 801-820页

作者： Mallory Little Moumita Dutta Hao Li Adam Matson Xiaojian Shi Gabby Mascarinas Bruk Molla Kris Weigel Haiwei Gu Sridhar Mani Julia Yue Cui Department of Environmental and Occupational Health Sciences University of WashingtonSeattleWA 98105USA Department of Medicine Molecular Pharmacology and GeneticsAlbert Einstein College of MedicineBronxNY 10461USA University of Connecticut HartfordCT 06106USA Arizona Metabolomics Laboratory College of Health SolutionsArizona State UniversityPhoenixAZ 85004USA

Pharmacological activation of the xenobiotic-sensing nuclear receptors pregnane X receptor(PXR) and constitutive androstane receptor(CAR) is well-known to increase drug metabolism and reduce inflammation. Little is known regarding their physiological functions on the gut microbiome. In this study, we discovered bivalent hormetic functions of PXR/CAR modulating the richness of the gut microbiome using genetically engineered mice. The absence of PXR or CAR increased microbial richness, and absence of both receptors synergistically increased microbial richness. PXR and CAR deficiency increased the pro-inflammatory bacteria Helicobacteraceae and Helicobacter. Deficiency in both PXR and CAR increased the relative abundance of Lactobacillus, which has bile salt hydrolase activity, corresponding to decreased primary taurine-conjugated bile acids(BAs) in feces, which may lead to higher internal burden of taurine and unconjugated BAs, both of which are linked to inflammation, oxidative stress, and cytotoxicity. The basal effect of PXR/CAR on the gut microbiome was distinct from pharmacological and toxicological activation of these receptors. Common PXR/CAR-targeted bacteria were identified, the majority of which were suppressed by these receptors. h PXR-TG mice had a distinct microbial profile as compared to wild-type mice. This study is the first to unveil the basal functions of PXR and CAR on the gut microbiome.

关键词： PXR CAR Gut microbiome Bile acids Inflammation Mice nuclear receptor Feces

Transcriptional Crosstalk between nuclear receptors and Cytokine Signal Transduction Pathways in Immunity

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Cellular & Molecular Immunology 2004年第6期1卷 416-424页

作者： LihuaWang XiaohuZhang WilliamL.Farrar BasicResearchProgram SAIC-FrederickNationalCancerInstitute-FrederickFrederickUSA. CytokineMolecularMechanismsSection LaboratoryofMolecularImmunoregulationDivisionofBasicSciencesNationalCancerInstitute-FrederickFrederickUSA.

The nuclear receptor superfamily and the transcriptional factors associated with cytokines are inherently different families of signaling molecules and activate gene transcription by binding to their respective responsive ***,it has become increasingly clear from our works and others that nuclear receptors are important regulators of cytokine production and function through complex and varied interactions between these distinct transcriptional *** review provides a general overview of the mechanism of action of nuclear receptors and their transcriptional crosstalk with transcriptional factors associated with cytokine transduction *** of the most important mechanistic aspects is protein to protein interaction through a direct or co-regulator-mediated indirect *** crosstalk is crucially involved in physiological and therapeutic roles of nuclear receptors and their iigands in immunity, inflammation and cytokine-related *** & Molecular Immunology.2004;1(6):416-424.

关键词： nuclear receptor cytokine signaling transduction crosstalk transcriptional factor immunity

Endocrine pheromones couple fat rationing to dauer diapause through HNF4αnuclear receptors

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Science China(Life Sciences) 2021年第12期64卷 2153-2174页

作者： Cheng Gao Qi Li Jialei Yu Shiwei Li Qingpo Cui Xiao Hu Lifeng Chen Shaobing O.Zhang Laboratory of Metabolic Genetics College of Life SciencesCapital Normal UniversityBeijing 100048China

Developmental diapause is a widespread strategy for animals to survive seasonal starvation and environmental *** animals often ration body fat to generate a basal level of energy for enduring *** diapause and fat rationing are coupled,however,is poorly *** nematode Caenorhabditis elegans excretes pheromones to the environment to induce a diapause form called dauer *** saturated forward genetic screens and CRISPR knockout,we found that dauer pheromones feed back to repress the transcription of ACOX-3,MAOC-1,DHS-28,DAF-22(peroxisomalβ-oxidation enzymes dually involved in pheromone synthesis and fat burning),ALH-4(aldehyde dehydrogenase for pheromone synthesis),PRX-10 and PRX-11(peroxisome assembly and proliferation factors).Dysfunction of these pheromone enzymes and factors relieves the ***,transcription is repressed not by pheromones excreted but by pheromones endogenous to each *** endogenous pheromones regulate the nuclear translocation of HNF4αfamily nuclear receptor NHR-79 and its co-receptor NHR-49,and,repress transcription through the two *** feedback repression maintains pheromone homeostasis,increases fat storage,decreases fat burning,and prolongs dauer ***,the exocrine dauer pheromones possess an unexpected endocrine function to mediate a peroxisome-nucleus crosstalk,coupling dauer diapause to fat rationing.

关键词： dauer diapause pheromone fatty acidβ-oxidation peroxisome nuclear receptor

Crosstalk between CYP2E1 and PPARα substrates and agonists modulate adipose browning and obesity

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2224-2238页

作者： Youbo Zhang Tingting Yan Tianxia Wang Xiaoyan Liu Keisuke Hamada Dongxue Sun Yizheng Sun Yanfang Yang Jing Wang Shogo Takahashi Qiong Wang Kristopher W.Krausz Changtao Jiang Cen Xie Xiuwei Yang Frank J.Gonzalez State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural Medicines School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Laboratory of Metabolism Center for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA School of Life Science and Engineering Lanzhou University of TechnologyLanzhou 730050China Department of Physiology and Pathophysiology School of Basic Medical SciencesPeking Universitythe Key Laboratory of Molecular Cardiovascular ScienceMinistry of EducationBeijing 100191China

Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been *** ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2 E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2 E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha(PPARa) target genes,including fibroblast growth factor(FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2 e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2 E1 and to serve as PPARa agonists, thus explaining how CYP2 E1 deficiency causes hepatic PPARa activation through increasing cellular levels of endogenous PPARa agonists. Translationally, a CYP2 E1 inhibitor was found to activate the PPARa-FGF21-beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Pparanull mice. The present results establish a metabolic crosstalk between PPARa and CYP2 E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2 E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.

关键词： CYP2E1 PPARa FGF21 Metabolic enzyme nuclear receptor Obesity

Chromatin remodeling regulated by steroid and nuclear receptors

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Cell Research 1997年第2期7卷 127-142页

作者： ALAN P WOLFFE(Laboratory of Molecular Embroyology Nat’l Institute ofChild Health and Human Development NIH Bldg, 18T,Rm. 106 Bethesda, MD 20892-5431 USA. e-mail:awlme @helix. nih.gov) Laboratory of Molecular Embroyology Nat'l Institute of Child Health and Human Development NIH USA

Coactivators and corepressors regulate transcriptionby controlling interactions between sequence-specific transcription factors, the basal transcriptional machinery andthe chromatin environment. This review consider the access of nuclear and steroid receptors to chromatin, theiruse of corepressors and coactivators to modify chromatinstructure and the implications for transcriptional *** assembly of specific nucleoprotein architectures andtargeted histone modification emerge as central controlling elements for gene expression.

关键词： Steroid receptor nuclear receptor coactitvator corepressor transcriptional activation nucleosome positioning histone modification transcriptional repression

The F-box-only protein 44 regulates pregnane X receptor protein level by ubiquitination and degradation

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4523-4534页

作者： Rebecca R.Florke Gee Andrew D.Huber Jing Wu Richa Bajpai Allister J.Loughran Shondra M.Pruett-Miller Taosheng Chen Department of Chemical Biology and Therapeutics St.Jude Children's Research HospitalMemphisTN 38105USA Graduate School of Biomedical Sciences St.Jude Children's Research HospitalMemphisTN 38105USA Center for Advanced Genome Engineering and Department of Cell and Molecular Biology St.Jude Children's Research HospitalMemphisTN 38105USA

Pregnane X receptor(PXR)is a ligand-activated nuclear receptor that transcriptionally upregulates drug-metabolizing enzymes[e.g.,cytochrome P4503A4(CYP3A4)]and *** the regulation of PXR target genes is well-characterized,less is known about the regulation of PXR protein *** screening an RNAi library,we identified the F-box-only protein 44(FBXO44)as a novel E3ligase for *** abundance increases upon knockdown of FBXO44,and,inversely,decreases upon overexpression of *** analysis revealed that FBXO44 interacts with PXR,leading to its ubiquitination and proteasomal degradation,and we determined that the F-box associated domain of FBXO44 and the ligand binding domain of PXR are required for the functional *** summary,FBXO44 regulates PXR protein abundance,which has downstream consequences for CYP3A4 levels and drug-drug *** results of this study provide new insight into the molecular mechanisms that regulate PXR protein level and activity and suggest the importance of considering how modulating E3ubiquitin ligase activities will affect PXR-mediated drug metabolism.

关键词： PXR FBXO44 Ubiquitination Proteasomal degradation CYP3A4 Drug-drug interactions E3 ligase nuclear receptor

SIRT1 activation synergizes with FXR agonism in hepatoprotection via governing nucleocytoplasmic shuttling and degradation of FXR

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Acta Pharmaceutica Sinica B 2023年第2期13卷 559-576页

作者： Shuang Cui Huijian Hu An Chen Ming Cui Xiaojie Pan Pengfei Zhang Guangji Wang Hong Wang Haiping Hao State Key Laboratory of Natural Medicines Key Laboratory of Drug Metabolism&PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China

Farnesoid X receptor(FXR)is widely accepted as a promising target for various liver diseases;however,panels of ligands in drug development show limited clinical benefits,without a clear ***,we reveal that acetylation initiates and orchestrates FXR nucleocytoplasmic shuttling and then enhances degradation by the cytosolic E3 ligase CHIP under conditions of liver injury,which represents the major culprit that limits the clinical benefits of FXR agonists against liver *** inflammatory and apoptotic stimulation,enhanced FXR acetylation at K217,closed to the nuclear location signal,blocks its recognition by importin KPNA3,thereby preventing its nuclear ***,reduced phosphorylation at T442 within the nuclear export signals promotes its recognition by exportin CRM1,and thereby facilitating FXR export to the *** governs nucleocytoplasmic shuttling of FXR,resulting in enhanced cytosolic retention of FXR that is amenable to degradation by ***1 activators reduce FXR acetylation and prevent its cytosolic *** importantly,SIRT1 activators synergize with FXR agonists in combating acute and chronic liver *** conclusion,these findings innovate a promising strategy to develop therapeutics against liver diseases by combining SIRT1 activators and FXR agonists.

关键词： FXR nuclear receptor Acetylation Phosphorylation Nucleocytoplasmic shuttling Degradation Nonalcoholic steatohepatitis Combinatorial drugs

Gadd45b is required in part for the anti-obesity effect of constitutive androstane receptor(CAR)

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Acta Pharmaceutica Sinica B 2021年第2期11卷 434-441页

作者： Xinran Cai Ye Feng Meishu Xu Chaohui Yu Wen Xie Center for Pharmacogenetics and Department of Pharmaceutical Sciences University of PittsburghPittsburghPA 15261USA Department of Endocrinology and Metabolic Disease the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Department of Gastroenterology the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Department of Pharmacology and Chemical Biology University of PittsburghPittsburghPA 15261USA

Crosstalk between xenobiotic metabolism and energy metabolism in the liver has provided a potential opportunity to target xenobiotic receptors to treat metabolic *** of constitutive andro stane receptor(CAR),a xenobiotic-sensing nuclear receptor,has been shown to inhibit obesity,suppress hepatic gluconeogenesis,and ameliorate hyperglycemia in rodent models of obesity and type 2 ***,the underlying molecular mechanism remains to be *** growth arrest and DNA damage-inducible gene 45 b(Gadd45 b),a well-known anti-apoptotic factor,has been shown to be an inducible coactivator of CAR in promoting rapid liver *** is unknown whether the effect of CAR on energy metabolism depends on GADD45 *** the present study and by using a high fat diet(HFD)-induced obesity model,we show that reduced body weight gain and improved insulin sensitivity by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene(TCPOBOP)were markedly blunted in Gadd45 b knockout ***,the TCPOBOP-responsive inhibition of hepatic lipogenesis,gluconeogenesis,and adipose inflammation observed in wild type mice were largely abolished in Gadd45 b knockout *** conclude that Gadd45 b is required in part for the metabolic benefits of CAR activation.

关键词： Obesity Diabetes CAR Gadd45b Glucogenogenesis Lipogenesis Xenobiotics nuclear receptor

Targeting nuclear receptors and its regulators for cancer therapy

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Targeting nuclear receptors and its regulators for cancer th...