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Toxicol Sci. 2008 Nov;106(1):290-9. doi: 10.1093/toxsci/kfn165. Epub 2008 Aug 14.

Potential relationship between hepatobiliary osteopontin and peroxisome proliferator-activated receptor alpha expression following ethanol-associated hepatic injury in vivo and in vitro.

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  • 1Department of Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas 77843-4467, USA.

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.

PMID:
18703563
[PubMed - indexed for MEDLINE]
PMCID:
PMC2563144
Free PMC Article

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