Lipoxygenase (LOX) metabolites from arachidonic acid and linoleic acid have been implicated in atherosclerosis, inflammation, keratinocyte differentiation and tumour progression. We previously showed that peroxisome proliferator-activated receptors (PPARs) play a role in keratinocyte differentiation and that the PPARα ligand 8S-hydroxyeicosatetraenoic acid is important in this process. We hypothesized that blocking LOX activity would block PPAR-mediated keratinocyte differentiation. Three LOX inhibitors, nordihydroguaiaretic acid, quercetin and morin, were studied for their effects on primary keratinocyte differentiation and PPAR activity. All three LOX inhibitors blocked calcium-induced expression of the differentiation marker keratin 1. In addition, activity of a PPAR-responsive element was inhibited in the presence of all three inhibitors, and this effect was mediated primarily through PPARα and PPARγ. LOX inhibitors decreased the activity of a chimaeric PPAR-Gal4-ligand-binding domain reporter system and this effect was reversed by addition of PPAR ligands. Ligand-binding studies revealed that the LOX inhibitors bind directly to PPARs and demonstrate a novel mechanism for these inhibitors in altering PPAR-mediated gene expression.
Skip Nav Destination
Article navigation
September 2002
- PDF Icon PDF LinkFront Matter
Research Article|
September 15 2002
Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors
Philippe THUILLIER;
Philippe THUILLIER
∗Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, P.O. Box 789, Smithville, TX 78957, U.S.A.
Search for other works by this author on:
Alan R. BRASH;
Alan R. BRASH
†Department of Pharmacology, Vanderbilt University Medical School, Nashville, TN 37232, U.S.A.
Search for other works by this author on:
James P. KEHRER;
James P. KEHRER
‡Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, U.S.A.,
Search for other works by this author on:
Julie B. STIMMEL;
Julie B. STIMMEL
§Nuclear Receptor Systems Research, GlaxoSmithKline Inc., Research Triangle Park, NC 27709, U.S.A.,
Search for other works by this author on:
Lisa M. LEESNITZER;
Lisa M. LEESNITZER
§Nuclear Receptor Systems Research, GlaxoSmithKline Inc., Research Triangle Park, NC 27709, U.S.A.,
Search for other works by this author on:
Peiying YANG;
Peiying YANG
¶Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, U.S.A.
Search for other works by this author on:
Robert A. NEWMAN;
Robert A. NEWMAN
¶Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, U.S.A.
Search for other works by this author on:
Susan M. FISCHER
Susan M. FISCHER
1
∗Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, P.O. Box 789, Smithville, TX 78957, U.S.A.
1To whom correspondence should be addressed (e-mail sa83161@odin.mdacc.tmc.edu).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
March 05 2002
Revision Received:
April 24 2002
Accepted:
June 17 2002
Accepted Manuscript online:
June 17 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 366 (3): 901–910.
Article history
Received:
March 05 2002
Revision Received:
April 24 2002
Accepted:
June 17 2002
Accepted Manuscript online:
June 17 2002
Citation
Philippe THUILLIER, Alan R. BRASH, James P. KEHRER, Julie B. STIMMEL, Lisa M. LEESNITZER, Peiying YANG, Robert A. NEWMAN, Susan M. FISCHER; Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors. Biochem J 15 September 2002; 366 (3): 901–910. doi: https://doi.org/10.1042/bj20020377
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.