Lipids

, Volume 42, Issue 6, pp 491–497

Epidermal Lipoxygenase Products of the Hepoxilin Pathway Selectively Activate the Nuclear Receptor PPARα

  • Zheyong Yu
  • Claus Schneider
  • William E. Boeglin
  • Alan R. Brash
Original Article

DOI: 10.1007/s11745-007-3054-4

Cite this article as:
Yu, Z., Schneider, C., Boeglin, W.E. et al. Lipids (2007) 42: 491. doi:10.1007/s11745-007-3054-4

Abstract

Arachidonic acid can be transformed into a specific epoxyalcohol product via the sequential action of two epidermal lipoxygenases, 12R-LOX and eLOX3. Functional impairment of either lipoxygenase gene (ALOX12B or ALOXE3) results in ichthyosis, suggesting a role for the common epoxyalcohol product or its metabolites in the differentiation of normal human skin. Here we tested the ability of products derived from the epidermal LOX pathway to activate the peroxisome proliferator-activated receptors PPARα, γ, and δ, which have been implicated in epidermal differentiation. Using a dual luciferase reporter assay in PC3 cells, the 12R-LOX/eLOX3-derived epoxyalcohol, 8R-hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid, activated PPARα with similar in potency to the known natural ligand, 8S-hydroxyeicosatetraenoic acid (8S-HETE) (both at 10 μM concentration). In contrast, the PPARγ and PPARδ receptor isoforms were not activated by the epoxyalcohol. Activation of PPARα was also observed using the trihydroxy hydrolysis products (trioxilins) of the unstable epoxyalcohol. Of the four trioxilins isolated and characterized, the highest activation was observed with the isomer that is also formed by enzymatic hydrolysis of the epoxyalcohol. Formation of a ligand for the nuclear receptor PPARα may be one possibility by which 12R-LOX and eLOX3 contribute to epidermal differentiation.

Keywords

Lipoxygenase 12R-LOX eLOX3 HETE PPAR Ichthyosis Epidermis Epoxyalcohol Hepoxilin Trioxilin 

Abbreviations

HETE

Hydroxyeicosatetraenoic acid

HPETE

Hydroperoxyeicosatetraenoic acid

LOX

Lipoxygenase

8R,11R,12R-epoxyalcohol

8R-Hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid

PPAR

Peroxisome proliferator-activated receptor

RP-HPLC

Reversed phase high performance liquid chromatography

SP-HPLC

Straight phase high performance liquid chromatography

CP-HPLC

Chiral phase high performance liquid chromatography

TMS

Trimethylsilyl

NCIE

Non-bullous ichthyosiform erythroderma

Copyright information

© AOCS 2007

Authors and Affiliations

  • Zheyong Yu
    • 1
    • 2
  • Claus Schneider
    • 1
  • William E. Boeglin
    • 1
  • Alan R. Brash
    • 1
  1. 1.Division of Clinical Pharmacology, Department of PharmacologyVanderbilt University School of MedicineNashvilleUSA
  2. 2.Howard Hughes Medical InstituteWashington UniversitySt LouisUSA

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