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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Prevention of Ethanol-Induced Liver Injury in Rats by an Agonist of Peroxisome Proliferator-Activated Receptor-, Pioglitazone

Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan

Agonists of peroxisome proliferator-activated receptor (PPAR)- have been shown to reduce tumor necrosis factor- (TNF-)-induced insulin resistance. On the other hand, sensitization of Kupffer cells to lipopolysaccharide (LPS) and their production of TNF- are critical for progression of alcoholic liver injury. This study was intended to determine whether pioglitazone, a PPAR- 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- 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- in culture media of Kupffer cells enhanced CD14 expression, LPS-induced intracellular Ca²⁺ concentration response, and production of TNF-. These results indicate that pioglitazone prevents alcoholic liver injury through abrogation of Kupffer cell sensitization to LPS.

Address correspondence to: Dr. Nobuhiro Sato, Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail: nsato{at}med.juntendo.ac.jp

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