Peroxisome proliferators-activated alpha agonist treatment ameliorates hepatic damage in rats with obstructive jaundice: an experimental study

Abstract

Background: Peroxisome proliferators-activated receptor alpha (PPARalpha) activation modulates cholesterol metabolism and suppresses bile acid synthesis. This study aims to evaluate the effect of short-term administration of fenofibrate, a PPARalpha agonist, on proinflammatory cytokines, apoptosis, and hepatocellular damage in cholestasis.

Methods: Forty male Wistar rats were randomly divided into four groups: I = sham operated, II = bile duct ligation (BDL), III = BDL + vehicle (gum Arabic), IV = BDL + fenofibrate (100 mg/kg/day). All rats were sacrificed on 7th day after obtaining blood samples and liver tissue. Total bilirubin, aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), gamma-glutamyl transferase, (GGT), tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and total bile acid (TBA) in serum, and liver damage scores; portal inflammation, necrosis, bile duct number, in liver tissue were evaluated. Apoptosis in liver was also assessed by immunohistochemical staining.

Results: Fenofibrate administration significantly reduced serum total bilirubin, AST, ALT, ALP, and GGT, TNF-alpha, IL-1 beta levels, and TBA (P < 0.01). Hepatic portal inflammation, hepatic necrosis, number of the bile ducts and apoptosis in rats with BDL were more prominent than the sham-operated animals (P < 0.01). PPARalpha induction improved all histopathologic parameters (P < 0.01), except for the number of the bile duct, which was markedly increased by fenofibrate therapy (P < 0.01).

Conclusion: Short-term administration of fenofibrate to the BDL rats exerts beneficial effects on hepatocellular damage and apoptosis.

Figure 1

H & E-stained liver sections of sham operated (A) and BDL (B) rats demonstrate bile-duct dilation, polymorphonuclear cell infiltrate, bile-duct proliferation (arrow, HE × 20), (C) markedly inflammation, and (D) necrosis (arrow, HE × 200).

Figure 2

TUNEL-positive cells per field. Apoptosis in rats with BDL was significantly higher than sham-operated rats (P < 0.01, Kruskal-Wallis test). BDL = Bile duct ligation, BDL + F = BDL + fenofibrate, BDL + V = BDL + vehicle.