title: The constitutive androstane receptor activator 4-[(4R,6R)-4,6-diphenyl-1,3-dioxan-2-yl]-N,N-dimethylaniline inhibits the gluconeogenic genes PEPCK and G6Pase through the suppression of HNF4α and FOXO1 transcriptional activity.
abstract: OBJECTIVE
  The dual role of the constitutive androstane receptor (CAR) as both a xenosensor and a regulator of endogenous energy metabolism (lipogenesis and gluconeogenesis) has recently gained acceptance. Here, we investigated the effects of 4-[(4R,6R)-4,6-diphenyl-1,3-dioxan-2-yl]-N,N-dimethylaniline (transpDMA), an effective CAR activator, on the gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in rat livers.
  
  
  METHODS
  The effects of transpDMA were investigated in normal and high-fat diet-fed Wistar rats using real-time PCR, Western blotting, chromatin immunoprecipitation assays (ChIP), glucose tolerance test and insulin tolerance test.
  
  
  RESULTS
  The expression of the gluconeogenic enzymes PEPCK and G6Pase was repressed by transpDMA treatment under fasting conditions. Long-term CAR activation by transpDMA significantly reduced fasting blood glucose levels and improved glucose homeostasis and insulin sensitivity in high-fat diet-fed rats. The metabolic benefits of CAR activation by transpDMA may have resulted from the inhibition of hepatic gluconeogenic genes. ChIP assays demonstrated that transpDMA prevented the binding of forkhead box O1 (FOXO1) to insulin response sequences in the PEPCK and G6Pase gene promoters in rat livers. Moreover, transpDMA-activated CAR inhibited hepatocyte nuclear factor-4α (HNF4α) transactivation by competing with HNF4α for binding to the specific binding element (DR1-site) in the gluconeogenic gene promoters.
  
  
  CONCLUSIONS
  Our results provide evidence to support the conclusion that transpDMA inhibits the gluconeogenic genes PEPCK and G6Pase through suppression of HNF4α and FOXO1 transcriptional activity.
authors.affiliation: Institute of Molecular Biology and Biophysics SB RAMS, Novosibirsk, Russia.
authors.forename: A A
authors.initials: AA
authors.lastname: Yarushkin
authors.forename: E M
authors.initials: EM
authors.lastname: Kachaylo
authors.forename: V O
authors.initials: VO
authors.lastname: Pustylnyak
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000090702:Constitutive Androstane Receptor; D059305:Diet, High-Fat; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D005786:Gene Expression Regulation; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000008:administration & dosage; D005951:Glucose Tolerance Test; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006573:Heterocyclic Compounds, 1-Ring / Q000494:pharmacology; D007328:Insulin / Q000008:administration & dosage; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1
chemical_list: D000814:Aniline Compounds; D000090702:Constitutive Androstane Receptor; D051858:Forkhead Transcription Factors; D005947:Glucose; D005952:Glucose-6-Phosphatase; D051557:Hepatocyte Nuclear Factor 4; D006573:Heterocyclic Compounds, 1-Ring; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D018160:Receptors, Cytoplasmic and Nuclear; C000592353:4-(4,6-diphenyl-1,3-dioxan-2-yl)-N,N-dimethylaniline; C496594:Hnf4a protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C015157:N,N-dimethylaniline; C582554:Pck1 protein, rat