Regulation of cytochrome P450 2B10 (CYP2B10) expression in liver by peroxisome proliferator-activated receptor-β/δ modulation of SP1 promoter occupancy

Takayuki Koga, Pei Li Yao, Maryam Goudarzi, Iain A. Murray, Gayathri Balandaram, Frank J. Gonzalez, Gary H. Perdew, Albert J. Fornace, Jeffrey M. Peters

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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 in Pparβ/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.

Original languageEnglish (US)
Pages (from-to)25255-25263
Number of pages9
JournalJournal of Biological Chemistry
Volume291
Issue number48
DOIs
StatePublished - Nov 25 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Regulation of cytochrome P450 2B10 (CYP2B10) expression in liver by peroxisome proliferator-activated receptor-β/δ modulation of SP1 promoter occupancy'. Together they form a unique fingerprint.

Cite this