Abstract
Agonists of peroxisome proliferator-activated receptor (PPAR)-γ have been shown to reduce tumor necrosis factor-α (TNF-α)-induced insulin resistance. On the other hand, sensitization of Kupffer cells to lipopolysaccharide (LPS) and their production of TNF-α are critical for progression of alcoholic liver injury. This study was intended to determine whether pioglitazone, a PPAR-γ agonist, could prevent alcohol-induced liver injury. Rats were given ethanol (5 g/kg b.wt.) and pioglitazone (500 μg/kg) once every 24 h intragastrically. Ethanol for 8 weeks caused pronounced steatosis, necrosis, and inflammation in the liver. These pathological parameters were diminished greatly by pioglitazone. Kupffer cells were sensitized to LPS after ethanol for 4 weeks as evidenced by aggravation of liver pathology induced by LPS (5 mg/kg) and enhancement of LPS (100 ng/ml)-induced intracellular Ca2+ concentration elevation in Kupffer cells. The parameters were diminished by treatment with pioglitazone. LPS-induced TNF-α production by Kupffer cells from the 4-week ethanol group was 3 to 4 times higher than control. This increase was blunted by 70% with pioglitazone. Gut permeability was 10-fold higher in the 4-week ethanol group, and pioglitazone treatment did not change the value. Inclusion of TNF-α in culture media of Kupffer cells enhanced CD14 expression, LPS-induced intracellular Ca2+ concentration response, and production of TNF-α. These results indicate that pioglitazone prevents alcoholic liver injury through abrogation of Kupffer cell sensitization to LPS.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.102.047217.
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ABBREVIATIONS: LPS, lipopolysaccharide; TNF-α, tumor necrosis factor-α; PPAR, peroxisome proliferator-activated receptor; i.g., intragastrically; AST, aspartate transaminase; ALT, alanine aminotransferase; [Ca2+]i, intracellular calcium concentration; AM, acetoxymethyl ester; ELISA, enzyme-linked immunosorbent assay; TTP, tristetraprolin; ANOVA, analysis of variance; HRP, horseradish peroxidase.
- Received March 17, 2003.
- Accepted May 27, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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