title: Effect of a high-fat diet on the hepatic expression of nuclear receptors and their target genes: relevance to drug disposition.
abstract: More than 1·4 billion individuals are overweight or obese worldwide. While complications often require therapeutic intervention, data regarding the impact of obesity on drug disposition are scarce. As the influence of diet-induced obesity on drug transport and metabolic pathways is currently unclear, the objective of the present study was to investigate the effect of high fat feeding for 13 weeks in female Sprague-Dawley rats on the hepatic expression of the nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), liver X receptor (LXR) and farnesoid X receptor (FXR) and several of their target genes. We hypothesised that high fat feeding would alter the gene expression of major hepatic transporters through a dysregulation of the expression of the nuclear receptors. The results demonstrated that, along with a significant increase in body fat and weight, a high-fat diet (HFD) induced a significant 2-fold increase in the expression of PXR as well as a 2-, 5- and 2·5-fold increase in the hepatic expression of the PXR target genes Abcc2, Abcb1a and Cyp3a2, respectively (P< 0·05). The expression levels of FXR were significantly increased in rats fed a HFD in addition to the increase in the expression levels of FXR target genes Abcb11 and Abcb4. The expression levels of both LXRα and LXRβ were slightly but significantly increased in rats fed a HFD, and the expression levels of their target genes Abca1 and Abcg5, but not Abcg8, were significantly increased. The expression of the nuclear receptor CAR was not significantly altered between the groups. This suggests that a HFD may induce changes in the hepatobiliary transport and metabolism of endogenous and exogenous compounds.
authors.affiliation: Department of Pharmaceutical Sciences,Leslie Dan Faculty of Pharmacy, University of Toronto,Toronto,ON,CanadaM5S 3M2.
authors.forename: Ragia H
authors.initials: RH
authors.lastname: Ghoneim
authors.affiliation: Department of Kinesiology,University of Montreal,QC,Canada.
authors.forename: Emilienne T
authors.initials: ET
authors.lastname: Ngo Sock
authors.affiliation: Department of Kinesiology,University of Montreal,QC,Canada.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lavoie
authors.affiliation: Department of Pharmaceutical Sciences,Leslie Dan Faculty of Pharmacy, University of Toronto,Toronto,ON,CanadaM5S 3M2.
authors.forename: Micheline
authors.initials: M
authors.lastname: Piquette-Miller
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D015870:Gene Expression; D008658:Inactivation, Metabolic / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D009765:Obesity / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics; D050177:Overweight / Q000378:metabolism; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011987:Receptors, Steroid / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D000099150:Receptor, Farnesoid X-Activated; C423013:Abcc2 protein, rat; C000605215:Nr1h3 protein, rat; C095122:multidrug resistance protein 3; C465260:Cyp3a2 protein, rat
keywords: P-glycoprotein