title: Farnesoid X receptor directly regulates xenobiotic detoxification genes in the long-lived Little mice.
abstract: Activation of xenobiotic metabolism pathways has been linked to lifespan extension in different models of aging. However, the mechanisms underlying activation of xenobiotic genes remain largely unknown. Here we showed that although farnesoid X receptor (FXR, Nr1h4) mRNA levels do not change significantly, FXR protein levels are elevated in the livers of the long-lived Little mice, leading to increased DNA binding activity of FXR. Hepatic FXR expression is sex-dependent in wild-type mice but not in Little mice, implying that up-regulation of FXR might be dependent on the reduction of growth hormone in Little mice. Growth hormone treatment decreased hepatic expression of FXR and xenobiotic genes Abcb1a, Fmo3 and Gsta2 in both wild-type and Little mice, suggesting an association between FXR and xenobiotic gene expression. We found that Abcb1a is transactivated by FXR via direct binding of FXR/retinoid X receptor α (RXRα) heterodimer to a response element at the proximal promoter. FXR also positively controls Fmo3 and Gsta2 expression through direct interaction with the response elements in these genes. Our study demonstrates that xenobiotic genes are direct transcriptional targets of FXR and suggests that FXR signaling may play a critical role in the lifespan extension observed in Little mice.
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, United States. Electronic address: yanjunj@bcm.tmc.edu.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Jiang
authors.forename: Jingling
authors.initials: J
authors.lastname: Jin
authors.forename: Polina
authors.initials: P
authors.lastname: Iakova
authors.forename: Julio Cesar
authors.initials: JC
authors.lastname: Hernandez
authors.forename: Nicole
authors.initials: N
authors.lastname: Jawanmardi
authors.forename: Emily
authors.initials: E
authors.lastname: Sullivan
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
authors.forename: Nikolai A
authors.initials: NA
authors.lastname: Timchenko
authors.forename: Gretchen J
authors.initials: GJ
authors.lastname: Darlington
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019281:Dimerization; D005260:Female; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008136:Longevity; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D018013:Receptors, Neuropeptide / Q000235:genetics; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D015533:Transcriptional Activation; D015262:Xenobiotics / Q000737:chemistry*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D005982:Glutathione Transferase; D013006:Growth Hormone; D007527:Isoenzymes; D018160:Receptors, Cytoplasmic and Nuclear; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D047490:Retinoid X Receptor alpha; D015262:Xenobiotics; D000099150:Receptor, Farnesoid X-Activated; C095122:multidrug resistance protein 3; C119995:glutathione S-transferase alpha; C048250:somatotropin releasing hormone receptor
keywords: CDCA; ChIP; DMSO; DR; EMSA; ER; FXR; FXR response elements; FXREs; GH; Ghrhr; Growth hormone; IGF; IR; Little mice; PCR; RXR; TSS; Xenobiotic detoxification gene; chenodeoxycholic acid; chromatin immunoprecipitation assay; dimethyl sulfoxide; direct repeat; electrophoresis mobility shift assay; everted repeat; farnesoid X receptor; growth hormone; growth hormone-releasing hormone receptor; insulin-like growth factor; inverted repeat; polymerase-chain reaction; retinoid X receptor; transcriptional start site