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 CCl 4 -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 CCl 4 -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.

Low Doses of Insulin-Like Growth Factor-I Induce Mitochondrial Protection in Aging Rats

“…Together, these data suggest an extramitochondrial protection of mitochondria, which is not fully understood. Previously, we reported that low doses of IGF-I restored the expression of several protease inhibitors such us ␣-1-antichymotripsin, the serine protease inhibitor 2 in cirrhotic rats (35), which could contribute to the described mitochondrial protection. In agreement with these results, it has been re- (28,29).…”

Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal

“…In a related finding, IGF-1 has been shown to promote recovery from carbon tetrachloride-induced cirrhosis, by increasing DNA methylation and normalizing gene expression. 55 As illustrated in Figure 7, MS has two substrates, homocysteine and the dopamine D4 receptor in its homocysteine state. Dopamine-stimulated PLM, measured with [ 14 C]formate, reflects D4 receptor-directed MS activity and ethanol increases dopamine-stimulated PLM (Figure 4d), in contrast to its inhibition of homocysteine-directed MS activity (Table 1).…”

Protection Against Oxidative Stress and “IGF-I Deficiency Conditions”

“…In agreement with these results, it has been reported that IGF-I differentially regulates Bcl-xL and Bax. Previously, we reported that low doses of IGF-I restored the expression of several protease inhibitors such us the serine protease inhibitor 2 in cirrotic rats [137], which could contribute to the described mitochondrial protection. Our work provides new evidence of beneficial effect of IGF-I replacement therapy in degenerative diseases including aging.…”

“…Experimental model of cirrhosis: Male Wistar rats in which liver cirrhosis was inducted using CCl4. IGF-I therapy or saline was administrated the last 4 weeks [2,6,41,[137][138][139]. b.…”