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

J Biol Chem. 2016 Nov 25;291(48):25255-25263. doi: 10.1074/jbc.M116.755447. Epub 2016 Oct 20.

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.

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / biosynthesis*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Cytochrome P450 Family 2 / biosynthesis*
  • Cytochrome P450 Family 2 / genetics
  • Ethanol / toxicity
  • Gene Expression Regulation, Enzymologic*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Kupffer Cells / metabolism
  • Kupffer Cells / pathology
  • Liver / metabolism*
  • Liver / pathology
  • Liver Diseases, Alcoholic / genetics
  • Liver Diseases, Alcoholic / metabolism*
  • Liver Diseases, Alcoholic / pathology
  • Mice
  • Mice, Knockout
  • PPAR delta / genetics
  • PPAR delta / metabolism*
  • PPAR-beta / genetics
  • PPAR-beta / metabolism*
  • Promoter Regions, Genetic*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Sp1 Transcription Factor / genetics
  • Sp1 Transcription Factor / metabolism*
  • Steroid Hydroxylases / biosynthesis*
  • Steroid Hydroxylases / genetics

Substances

  • PPAR delta
  • PPAR-beta
  • Sp1 Transcription Factor
  • Ethanol
  • Steroid Hydroxylases
  • Aryl Hydrocarbon Hydroxylases
  • Cyp2b10 protein, mouse
  • Cytochrome P450 Family 2