| First Author | Koga T | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 48 | Pages | 25255-25263 |
| PubMed ID | 27765815 | Mgi Jnum | J:237627 |
| Mgi Id | MGI:5816390 | Doi | 10.1074/jbc.M116.755447 |
| Citation | Koga T, et al. (2016) Regulation of Cytochrome P450 2B10 (CYP2B10) Expression in Liver by Peroxisome Proliferator-activated Receptor-beta/delta Modulation of SP1 Promoter Occupancy. J Biol Chem 291(48):25255-25263 |
| abstractText | Alcoholic liver disease is a pathological condition caused by overconsumption of alcohol. Because of the high morbidity and mortality associated with this disease, there remains a need to elucidate the molecular mechanisms underlying its etiology and to develop new treatments. Because peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) modulates ethanol-induced hepatic effects, the present study examined alterations in gene expression that may contribute to this disease. Chronic ethanol treatment causes increased hepatic CYP2B10 expression inPparbeta/delta+/+ mice but not in Pparbeta/delta-/- mice. Nuclear and cytosolic localization of the constitutive androstane receptor (CAR), a transcription factor known to regulate Cyp2b10 expression, was not different between genotypes. PPARgamma co-activator 1alpha, a co-activator of both CAR and PPARbeta/delta, was up-regulated in Pparbeta/delta+/+ liver following ethanol exposure, but not in Pparbeta/delta-/- liver. Functional mapping of the Cyp2b10 promoter and ChIP assays revealed that PPARbeta/delta-dependent modulation of SP1 promoter occupancy up-regulated Cyp2b10 expression in response to ethanol. These results suggest that PPARbeta/delta regulates Cyp2b10 expression indirectly by modulating SP1 and PPARgamma co-activator 1alpha expression and/or activity independent of CAR activity. Ligand activation of PPARbeta/delta attenuates ethanol-induced Cyp2b10 expression in Pparbeta/delta+/+ liver but not in Pparbeta/delta-/- liver. Strikingly, Cyp2b10 suppression by ligand activation of PPARbeta/delta following ethanol treatment occurred in hepatocytes and was mediated by paracrine signaling from Kupffer cells. Combined, results from the present study demonstrate a novel regulatory role of PPARbeta/delta in modulating CYP2B10 that may contribute to the etiology of alcoholic liver disease. |
