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J Biol Chem. 2016 Nov 25;291(48):25255-25263. Epub 2016 Oct 20.

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

Author information

1
From the Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, Pennsylvania 16802.
2
the Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, D. C., 20057, and.
3
the Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland 20892.
4
From the Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, Pennsylvania 16802, jmp21@psu.edu.

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

KEYWORDS:

Kupffer cells; alcoholic liver disease; cytochrome P450; cytochrome P450 2B10; gene regulation; liver; liver injury; peroxisome proliferator-activated receptor (PPAR); peroxisome proliferator-activated receptor-β/δ

PMID:
27765815
PMCID:
PMC5122791
DOI:
10.1074/jbc.M116.755447
[Indexed for MEDLINE]
Free PMC Article

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