Prevention of ethanol-induced liver injury in rats by an agonist of peroxisome proliferator-activated receptor-gamma, pioglitazone.
Agonists of peroxisome proliferator-activated receptor (PPAR)-gamma have been shown to reduce tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance. On the other hand, sensitization of Kupffer cells to lipopolysaccharide (LPS) and their production of TNF-alpha are critical for progression of alcoholic liver injury. This study was intended to determine whether pioglitazone, a PPAR-gamma agonist, could prevent alcohol-induced liver injury. Rats were given ethanol (5 g/kg b.wt.) and pioglitazone (500 microg/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-alpha 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-alpha in culture media of Kupffer cells enhanced CD14 expression, LPS-induced intracellular Ca2+ concentration response, and production of TNF-alpha. These results indicate that pioglitazone prevents alcoholic liver injury through abrogation of Kupffer cell sensitization to LPS.
Enomoto
Nobuyuki
N
Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan. nsato@med.juntendo.ac.jp
Takei
Yoshiyuki
Y
Hirose
Miyoko
M
Konno
Akira
A
Shibuya
Tomoyoshi
T
Matsuyama
Shujiro
S
Suzuki
Satoko
S
Kitamura
Kenichi Ikejima Tsuneo
KI
Sato
Nobuhiro
N
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004347:Drug Interactions; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008108:Liver Diseases, Alcoholic / Q000517:prevention & control*; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013844:Thiazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007004:Hypoglycemic Agents; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D002118:Calcium; D000077205:Pioglitazone