INHIBITION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-a (PPAR-a) REDUCES PROLIFERATION OF PRENEOPLASTIC LIVER FOCI

CASELLA M; MONTI J A; PARODY J P; CEBALLOS M P; INGARAMO P I; FRANCÉS D E; RONCO M T; PISANI G; CARNOVALE C E; CARRILLO M C; ALVAREZ M L

Barcelona

Congreso; 47th annual meeting of the European Association for the Study of the Liver (EASL).; 2012

PPAR-alfa is a ligand-activated transcriptional factors expressed in liver, kidney, small intestine, heart, and muscle, where it is involved in fatty acids and carbohydrates metabolism, wound healing, vascular homeostasis, and differentiation and cellular proliferation of normal and neoplastic tissues. The relationship between cancer and PPAR-alfa is not fully understood. Some studies postulate PPAR-alfa has carcinogenic properties, whereas others have demonstrated anti-neoplastic and anti-angiogenic activities of this nuclear receptor. The aim of this work was to study the effect of PPAR-alfa inhibition on the development of rat preneoplasic liver foci, in order to clarify its role in hepatocarcinogenesis.Adult male Wistar rats were subjected to iniciation-promotion model of hepatocarcinogenesis (IP). A group of IP rats was treated with quercetin (competitive inhibitor of PPAR-alfa activation). The doses of quercetin used were 10 (Q10) and 20 (Q20) mg/kg body weight.Western blot assays were performed to confirm PPAR-alfa inhibition by quercetin. Results showed a significant reduction of PPAR-alaf protein levels in Q20 group (IP: 100±12; Q10: 78±20; Q20: 29±07*). Preneoplastic foci were detected by immunofluorescence and confocal microscopy by using the antibody raised against the placental form of glutathione S-transferase. Immunodetection and quantification of preneoplastic foci showed a significant decrease in their number and size in Q20 group (number foci/mm2: IP= 12.7±1.0; Q10= 10.5±1.5; Q20= 6.1±0.6*, % of liver occupied by foci: IP= 3.8±0.6; Q10= 3.6±0.1; Q20= 1.6±0.6*). The proliferative index (PI) in the foci was determined by immunohistochemical detection of proliferating cell nuclear antigen (PCNA). PI was significantly reduced in Q20 (IP: 28.8±1.2; Q20: 21.9±0.9*). Moreover, the percentage of PCNA-positive preneoplastic hepatocytes in S and M phases of the cell cycle were lower in Q20 group (%S: IP: 2.0±0.2; Q20: 4.1±0.2*; %M: IP: 2.4±0.2; Q20: 1.2±0.2*) (*p< 0.05).In conclusion, PPAR-alfa inhibition by quercetin during the development of liver tumorigenesis prevents the development of preneoplastic lesions, with reduction of the proliferation rates into the foci. These results strongly suggest that blockage of PPAR-alfa activation could be useful for new preventive and therapeutic strategies against liver tumors.