Regulation of Cytochrome P450 2B10 (CYP2B10) Expression in Liver by Peroxisome Proliferator-activated Receptor-?/? Modulation of SP1 Promoter Occupancy.

ABSTRACT: 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-?/? (PPAR?/?) 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 inPpar?/?+/+ mice but not in Ppar?/?-/- mice. Nuclear and cytosolic localization of the constitutive androstane receptor (CAR), a transcription factor known to regulate Cyp2b10 expression, was not different between genotypes. PPAR? co-activator 1?, a co-activator of both CAR and PPAR?/?, was up-regulated in Ppar?/?+/+ liver following ethanol exposure, but not in Ppar?/?-/- liver. Functional mapping of the Cyp2b10 promoter and ChIP assays revealed that PPAR?/?-dependent modulation of SP1 promoter occupancy up-regulated Cyp2b10 expression in response to ethanol. These results suggest that PPAR?/? regulates Cyp2b10 expression indirectly by modulating SP1 and PPAR? co-activator 1? expression and/or activity independent of CAR activity. Ligand activation of PPAR?/? attenuates ethanol-induced Cyp2b10 expression in Ppar?/?+/+ liver but not in Ppar?/?-/- liver. Strikingly, Cyp2b10 suppression by ligand activation of PPAR?/? 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 PPAR?/? in modulating CYP2B10 that may contribute to the etiology of alcoholic liver disease.

SUBMITTER: Koga T 

PROVIDER: S-EPMC5122791 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature