Abstract
Liver cirrhosis (LC) is a kind of liver disease which is pathologically characterized by abnormality and necrosis of hepatic cells, proliferation of fibrous tissue, nodular regeneration and pseudolobule formation. To explore the mechanism of LC occurrence at the level of mRNA, Rat Genome 230 2.0 Array was used to detect gene expression profiles of rat fibrotic livers in 3, 6 and 9 weeks after CCl4 treatment in this study. It was found that a total of 305 genes including 153 up-regulated, 150 down-regulated and 2 up/down-regulated genes, were related to LC occurrence. Then, k-means clustering was employed to classify above 305 genes into 5 clusters based on gene expression similarity, and EASE analysis further indicated that the above genes were mainly associated with metabolic process, stress reaction, cell growth and apoptosis/death. Thereafter, ingenuity pathway analysis (IPA) software was used to analyze potential effects of the above-mentioned 305 genes, and the results suggested that lipid metabolism and cell growth were inhibited while cell apoptosis/death was activated, but immune/inflammatory response was first activated and then inhibited. Furthermore, IPA also predicted that several signal pathways “ERK/MAPK Signaling”, “p38 MAPK”, “Endothelin-1 Signaling”, “Growth Hormone Signaling”, “LPS/IL-1-mediated inhibition of RXR function” and “IL-6 Signaling” were involved in regulating the occurrence of liver cirrhosis. It was concluded that 305 genes and 3 kinds of physiological activities were closely related to LC occurrence. Key words: Liver cirrhosis, gene expression profile, systems biology analysis, physiological activity.
Highlights
Liver cirrhosis (LC), a chronic liver disease of progression and diffusivity, is usually caused by viral hepatitis, longterm excessive drinking, long-term cholestasis, chemical toxin or drugs, liver congestion, parasitosis, genetic and metabolic diseases, etc., which are able to trigger the following processes: apoptosis and compensatory regeneration of hepatocytes (Zhou et al, 2014)
Thereafter, ingenuity pathway analysis (IPA) software was used to analyze potential effects of the above-mentioned 305 genes, and the results suggested that lipid metabolism and cell growth were inhibited while cell apoptosis/death was activated, but immune/inflammatory response was first activated and inhibited
In the third week of LC group induced by CCl4, central venous was congested obviously, and spotty necrosis was observed with increased number of cells undergoing hydropic degeneration (Figure 1B)
Summary
Liver cirrhosis (LC), a chronic liver disease of progression and diffusivity, is usually caused by viral hepatitis, longterm excessive drinking, long-term cholestasis, chemical toxin or drugs, liver congestion, parasitosis, genetic and metabolic diseases, etc., which are able to trigger the following processes: apoptosis and compensatory regeneration of hepatocytes (Zhou et al, 2014). The sustained liver damages induced by the above-mentioned factors can activate hepatic stellate cells (HSCs), and result in over abundant synthesis and insufficient degradation of collagens (Pereira et al, 2010). Tumor necrosis factor alpha (TNFα) and transforming growth factor beta (TGFβ) could stimulate activation of HSCs, which are known to be activated as the predominant cells responsible for liver fibrosis. Chou et al (2006) demonstrated that IL-10 inhibited fibrogenic and pro-inflammatory gene responses in CCl4induced mice, and Zhang et al (2007) showed that IL-10 presented an anti-fibrogenic effect by down-regulating the activity of HSCs. CCl4 is widely used for inducing liver fibrosis and cirrhosis in animal models, leading to the production of CCl3 and CCl3OO· free radicals (Chavez et al, 2012). The small sample size and heterogeneous patient characteristics may limit the conclusions, more gene symbols need further investigation
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