Skip Navigation


ToxSci Advance Access originally published online on August 14, 2008
Toxicological Sciences 2008 106(1):290-299; doi:10.1093/toxsci/kfn165
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
106/1/290    most recent
kfn165v2
kfn165v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Lee, J.-H.
Right arrow Articles by Ramaiah, S. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, J.-H.
Right arrow Articles by Ramaiah, S. K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Potential Relationship between Hepatobiliary Osteopontin and Peroxisome Proliferator–Activated Receptor {alpha} Expression following Ethanol-Associated Hepatic Injury In Vivo and In Vitro

Jin-Hyung Lee*, Atrayee Banerjee*, Yoshi Ueno{dagger} and Shashi K. Ramaiah*,1

* Department of Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas 77843-4467 {dagger} Division of Gastroenterology, Graduate School of Medicine, Tohoku University, Sendai, Japan

1 To whom correspondence should be addressed at the Biomarker & Clinical Pathology Lead, Pfizer-Drug Safety Research and Development, 645 S. Newstead Avenue, St Louis, MO 63110. Fax: (314) 274-7938. E-mail: shashi.ramaiah{at}pfizer.com.

Received May 1, 2008; accepted August 6, 2008


  Abstract

Osteopontin (OPN) up-regulation is known to mediate hepatic inflammation in a rodent model of alcoholic liver disease (ALD) and alcohol ingestion is reported to inhibit hepatic peroxisome proliferator–activated receptor-{alpha} (PPAR-{alpha}) activity leading to hepatic steatosis and inflammation. Therefore, the objective of this study was to investigate the potential relationship between the anti-inflammatory PPAR-{alpha} and proinflammatory OPN in rats and mice livers, and cell cultures of hepatocytes and biliary epithelium. Experiments were designed to evaluate the influence of ethanol (EtOH), lipopolysaccharide (LPS), and acetaldehyde (ACA) on OPN and PPAR-{alpha} expression levels in vivo (rats and mice) and in vitro (hepatocytes and biliary epithelium). Adult Sprague-Dawley rats and C57BL6 mice were fed EtOH-containing Lieber-DeCarli liquid diet for 6 weeks and injected with a single dose of LPS. A combination of EtOH and LPS treated rats and mice showed significant induction of hepatic OPN expression compared with the controls. Similarly, cells exposed to physiological doses of EtOH, LPS, a combination of EtOH and LPS, and ACA resulted in increased OPN protein and mRNA expression. Rats and mice in ALD model and cells treated with EtOH and ACA showed downregulation of PPAR-{alpha} mRNA. Also, DNA binding activity of PPAR-{alpha} to PPAR response element was significantly reduced following treatment. Overexpression of PPAR-{alpha} rescued the reduced PPAR-{alpha} activity and PPAR-{alpha} agonist, bezafibrate, elevated PPAR-{alpha} activity after treatment of EtOH, LPS, and ACA when cells were exposed by bezafibrate. To further delineate the potential relationship between OPN and PPAR-{alpha}, OPN–/– mice showed no change of PPAR-{alpha} mRNA level although wild-type mice showed downregulation of PPAR-{alpha} mRNA after EtOH treatment. In conclusion, the current study suggests that OPN is induced by EtOH and its metabolite ACA and opposite relationship likely exist between PPAR-{alpha} and OPN expression within the liver during ALD.

Key Words: bezafibrate; ethanol; osteopontin; peroxisome proliferator–activated receptor-{alpha}.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.