Pioglitazone ameliorates nonalcoholic steatohepatitis by down-regulating hepatic nuclear factor-kappa B and cyclooxygenases-2 expression in rats.

Abstract

BACKGROUND:

Pioglitazone is effective in nonalcoholic steatohepatitis (NASH), but the mechanisms of action are not completely understood. This study was designed to investigate the effects of pioglitazone on hepatic nuclear factor-kappa B (NF-κB) and cyclooxygenases-2 (COX-2) expression in NASH rats.

METHODS:

Thirty Sprague-Dawley male rats were randomly assigned to a control group (n = 10), NASH group (n = 10), and pioglitazone treatment group (n = 10). Liver tissues were processed for histology by hematoxylin & eosin and Masson stained. Serum alanine aminotransferase (ALT), cholesterol, triglyceride, fasting blood glucose (FBG), fasting insulin (FINS) levels and biochemical parameters of antioxidant enzyme activities, tumor necrosis factor alpha (TNF-α), prostaglandin E(2) (PGE(2)) levels in serum and liver were measured. The mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARγ), NF-κB and COX-2 were determined by real-time polymerase chain reaction, Western blotting and immunohistochemistry. One-way analysis of variance (ANOVA) and Wilcoxon's signed-rank test was used for the statistical analysis.

RESULTS:

There were severe steatosis, moderate inflammatory cellular infiltration and fibrosis in NASH rats. After pioglitazone treatment, steatosis, inflammation and fibrosis were significantly improved compared with the NASH group (χ(2) = 20.40, P < 0.001; χ(2) = 20.17, P < 0.001; χ(2) = 13.98, P = 0.002). Serum ALT, cholesterol, triglyceride, FBG, FINS levels were significantly elevated in the NASH group (P < 0.05). In the NASH group, total anti-oxidation competence (T-AOC), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-PX) and malondialdehyde (MDA) levels in serum and liver were conspicuous disordered than those parameters in the control group. Meanwhile, TNF-α and PGE(2) levels in serum and liver were significantly increased compared with the control group. Immunohistochemistry showed NF-κB and COX-2 expression in liver was significantly elevated. However, PPAR? level was decreased in the NASH group. Real-time PCR and Western blotting revealed mRNA and protein expression of COX-2 were increased in the NASH group compared with the control group (0.57 ± 0.08 vs. 2.83 ± 0.24; 0.38 ± 0.03 vs. 1.00 ± 0.03, P < 0.001 and P = 0.004, respectively). After pioglitazone intervention, all of those parameters markedly improved (P < 0.05 or P < 0.01).

CONCLUSION:

Down-regulating hepatic NF-κB and COX-2 expression, at least in part, is one of the possible therapeutic mechanisms of pioglitazone in NASH rats.

• Authors: Jia-Sheng Zhao, Feng-Shang Zhu, Su Liu, Chang-Qing Yang, Xi-Mei Chen
• Journal: Chinese medical journal (Chin Med J (Engl)) Vol. 125 Issue 13 Pg. 2316-21 (Jul 2012) ISSN: 2542-5641 [Electronic] China
• PMID: 22882855 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• PPAR gamma
• Thiazolidinediones
• Tumor Necrosis Factor-alpha
• Malondialdehyde
• Glutathione Peroxidase
• Cyclooxygenase 2
• Superoxide Dismutase
• Alanine Transaminase
• Pioglitazone

Topics

• Alanine Transaminase (blood, metabolism)
• Animals
• Cyclooxygenase 2 (genetics, metabolism)
• Fatty Liver (drug therapy, metabolism)
• Glutathione Peroxidase (metabolism)
• Male
• Malondialdehyde (blood, metabolism)
• NF-kappa B (genetics, metabolism)
• PPAR gamma (metabolism)
• Pioglitazone
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Real-Time Polymerase Chain Reaction
• Superoxide Dismutase (metabolism)
• Thiazolidinediones (therapeutic use)
• Tumor Necrosis Factor-alpha (blood, metabolism)