An adenosine derivative compound, IFC305, reverses fibrosis and alters gene expression in a pre-established CCl(4)-induced rat cirrhosis.
Cirrhosis is a complex process that involves a dynamic modification of liver cell phenotype associated to gene expression changes. This study investigates the reversing capacity of an adenosine derivative compound (IFC305) on a rat model of liver cirrhosis and gene expression changes associated with it. Rats were treated with IFC305 or saline for 5 or 10 weeks after cirrhosis induction (CCl(4) treatment for 10 weeks). Fibrosis score, collagenase activity and amount of hepatic stellate cells (HSC, activated and with a lipid-storing phenotype) were measured in livers. In addition, gene expression analysis was performed using 5K DNA microarrays and quantitative RT-PCR. Treatment of cirrhotic rats with IFC305 for 5 or 10 weeks compared to saline control, induced: (1) reduction of fibrosis (50-70%) and of collagen, of alpha-SMA and desmin proteins, as well as of activated HSCs in liver, (2) increased collagenase activity and cell number of lipid-storing HSC, (3) improved serum parameters of liver function, such as reduced activity of aminotransferases and bilirubin. Expression of 413 differential genes, deregulated in cirrhotic samples, tended to be normalized by IFC305 treatment. Some genes modulated at transcript level by IFC305 were Tgfb1, Fn1, Col1a1, C9, Apoa1, Ass1, Cps1, and Pparg. The present study shows that IFC305 reverses liver fibrosis through modulation of adipogenic and fibrosis-related genes and by ameliorating hepatic function. Thus, understanding of the anti-cirrhotic effect of IFC305 might have therapeutical potential in patients with cirrhosis.
Pérez-Carreón
Julio Isael
JI
Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Mexico 04510, D.F., Mexico; Instituto Nacional de Medicina Genómica (INMEGEN), Periférico sur 4214, Mexico, D.F., Mexico.
Martínez-Pérez
Lidia
L
Loredo
María Lilia
ML
Yañez-Maldonado
Lucia
L
Velasco-Loyden
Gabriela
G
Vidrio-Gómez
Susana
S
Ramírez-Salcedo
Jorge
J
Hernández-Luis
Francisco
F
Velázquez-Martínez
Israel
I
Suárez-Cuenca
Juan Antonio
JA
Hernández-Muñoz
Rolando
R
de Sánchez
Victoria Chagoya
VC
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives; D002251:Carbon Tetrachloride / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014508:Urea / Q000378:metabolism
C548964:adenosine 2-aminosuccinic acid-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol; D001224:Aspartic Acid; D014508:Urea; D002251:Carbon Tetrachloride; D000241:Adenosine