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doi:10.1016/j.yexmp.2007.10.001 
Published by Elsevier Inc.
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Meena R. Sharmaa, 
, 
, Rathnagiri Polavarapub, Daniel Rosemanb, Viraj Patelb, Eric Eatonb, P.B. Kavi Kishorb and Amin A. Nanjia, c
Received 16 March 2007;
Abstract
Alcoholic liver disease (ALD) is an increasingly recognized condition that may progress to end-stage liver disease. In addition to alcohol consumption, genetic factors, dietary fatty acids, gender and viral infection potentiate the severity of alcoholic liver injury. In humans, significant gender differences in susceptibility to ALD are observed. In the intragastric infusion rat model of ALD, female rats developed more severe liver injury than males. To understand the effect of gender on the development of more severe ALD in female rats, we performed a microarray based expression profiling of genes in rats fed with fish oil and ethanol diet. A large number of genes showed significant changes in female livers compared to males. The upregulated genes in female liver were involved in proteosome endopeptidase activity, catalytic activity, lipid metabolism, alcohol metabolism, mitochondrial and oxidoreductase activity. The downregulated genes were involved in oxidoreductase activity, chaperone activity, and electron transport activity in the female liver as demonstrated by biological theme analysis. Ingenuity computational pathway analysis tools were used to identify specific regulatory networks of genes operative in promoting liver injury. These networks allowed us to identify a large cluster of genes involved in lipid metabolism, development, cellular growth and proliferation, apoptosis, carcinogenesis and various signaling pathways. Genes listed in this article that were significantly increased or decreased (expression two fold or more) were assigned to pathological functional groups and reviewed for relevance to establish hypotheses of potential mechanisms involved in ALD in female liver injury.
Keywords: Alcoholic liver disease; Ingenuity computational pathway; Biological theme
Article Outline
- Introduction
- Materials and methods
- Animal model
- RNA isolation
- Microarray analysis
- Microarray data analysis
- Biological theme analysis
- Pathway analysis
- Real-time PCR
- Results and discussion
- Genes upregulated in female rats
- Genes downregulated in female rats
- Identification of biologically relevant networks
- Relevant pathways in the pathogenesis of ALD in females
- Verification of microarray results by real-time RT-PCR
- Genes relevant to promoting fatty liver
- Cytokines and inflammatory response
- Genes relevant to enhanced oxidant stress
- Cell cycle regulatory genes
- References
