Role of peroxisome proliferator activated receptor [PPAR] agonists in experimental liver fibrosis in rats

ABSTRACT

The ligand-dependent transcription factors, peroxisome proliferator-activated receptors [PPARs] are expressed in hepatic stellate cells [HSCs], which are the cells reported to play a central role in liver fibrosis. It has been reported that the transcriptional activity of PPAR gamma and alpha is reduced during activation of HSCs. The aim of the present study was to evaluate whether oral administration of pioglitazone [alpha PPAR gamma ligand], and bezafibrate [alpha PPAR alpha ligand], might retard liver fibrosis in rats. Fifty male albino rats weighing 150-200 g were used in the present study. Rats were divided into five groups, each often rats. Group I, injected intraperitonealy [i.p.] by thioacetamide [TAA]. Group II, injected i.p. by saline. Groups III and IV, treated with bezafibrate and pioglitazone respectively, orally starting from the first day of TAA administration. Group V, served as a control group for groups III and IV. The duration of the study was six weeks. Administration of TAA to rats for six weeks resulted in significant increases in portal pressure, serum cytokines [tumor necrosis factor-alpha TNF-alpha and transforming growth factor-beta 1 TGF-beta 1], hepatic hydroxyproline [HPO], and serum aspartate aminotransferase [AST] and alanine aminotransferase [ALT] associated with a significant decrease in hepatic glycogen concentration. On the other hand, the two PPAR ligands, pioglitazone and bezafibrate, produced a significant decrease in portal pressure, a significant decrease in serum TNF-alpha and TGF-beta 1, a significant improvement in all the estimated parameters of liver function, as well as a significant decrease in hepatic HPO concentration in rats that received the drugs for six weeks compared to the control untreated rats. The results of the present study demonstrated that the PPAR agonists, pioglitazone and bezafibrate were effective in preventing the fibrogenic process via modulating the action of the cytokines TNF-alpha and TGF- beta1. Further studies on humans are needed in order to assess the clinical use of PPAR agonists in patients with liver fibrosis