title: Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I.
abstract: We have previously shown that the administration of low doses of insulin-like growth factor-I (IGF-I) to CCl4-cirrhotic rats improves liver function and reduces fibrosis. To better understand the mechanisms behind the hepatoprotective effects of IGF-I, and to identify those genes whose expression is affected in cirrhosis and after IGF-1 treatment, we have performed differential display of mRNA analysis by means of polymerase chain reaction (PCR) in livers from control and CCl4-cirrhotic rats treated or not with IGF-I. We have identified 16 genes that were up- or down-regulated in the cirrhotic liver. IGF-I treatment partially normalized the expression of eight of these genes, including serine proteinase inhibitors such as serpin-2 and alpha-1-antichymotripsin, alpha-1-acid glycoprotein, and alpha-2u-globulin. Additionally, we show that IGF-I enhanced the regenerative activity in the cirrhotic liver, as determined by the increased expression of the proliferating cell nuclear antigen (PCNA). Finally, IGF-I treatment partially restored the expression of growth hormone receptor (GHR) and the levels of global genomic DNA methylation, which are reduced in human and experimental cirrhosis. Taken together, our observations confirm the hepatoprotective effects of IGF-I, and suggest that this action can be exerted in part through the normalization of liver gene expression, growth hormone (GH) responsiveness and global genomic DNA methylation.
authors.affiliation: División de Hepatología y Terapia Génica, Facultad de Medicina, Departamento de Medicina Interna, Universidad de Navarra, 31008, Pamplona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Mirpuri
authors.forename: Elena R
authors.initials: ER
authors.lastname: García-Trevijano
authors.forename: Inma
authors.initials: I
authors.lastname: Castilla-Cortazar
authors.forename: Carmen
authors.initials: C
authors.lastname: Berasain
authors.forename: Jorge
authors.initials: J
authors.lastname: Quiroga
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Ortigosa
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Matías A
authors.initials: MA
authors.lastname: Avila
mesh_terms: D000818:Animals; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D051542:Hepatocyte Nuclear Factor 3-beta; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000502:physiology*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D023081:CCAAT-Binding Factor; D004268:DNA-Binding Proteins; C496502:FOXA2 protein, human; C496504:Foxa2 protein, rat; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D011986:Receptors, Somatotropin; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta; D007334:Insulin-Like Growth Factor I; D002251:Carbon Tetrachloride