Abstract
Background/Aims: The mechanisms underlying alcohol-induced liver injury are not fully elucidated.
An approach in this direction would consist of an all-inclusive assessment of gene
expression in the liver. The purpose of this study was to perform a comprehensive
analysis of gene expression in the livers of mice treated with ethanol by means of
intragastric infusion.
Methods: An ethanol- or glucose-enriched liquid diet was fed to animals for 4 weeks via a
long-term gastrostomy catheter. The animals were killed and plasma alanine:2-oxoglutarate
aminotransferase (ALT) assay, liver histology and total RNA analysis by microarray
gene technology were performed.
Results: Alcohol increased ALT, induced steatosis, necrosis and inflammation. A total of
12,423 genes were analyzed for expression out of which 4867 were expressed by the
liver. Alcohol repressed expression of 11 genes, induced expression of 13 genes, and
up- or down-regulated expression of 44 and 42 genes >2-fold, respectively. Gene expression
analysis identified several genes that have not previously been tested for alcohol
effects.
Conclusions: This study: (i) expands the knowledge of mechanism(s) of action of ethanol; (ii)
indicates novel pathways of ethanol action on the liver, and (iii) illustrates the
utility of microarray gene analysis in hepatology research.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of HepatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Role of cytochrome P450 2E1 in alcohol liver disease pathogenesis.Alcohol. 1993; 10: 459-464
- Cytochrome P450 CYP 2E1 induction during chronic alcohol exposure occurs by a two-step mechanism associated with blood alcohol concentrations in rats.J Pharmacol Exp Ther. 1993; 264: 944-950
- Ethanol regulation of adenosine receptor-stimulated cAMP levels in a cloned cell line: an invitro model of cellular tolerance to ethanol.Proc Natl Acad Sci USA. 1986; 83: 2105-2108
- Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of induction of Bcl-2 and Bcl-XL proteins.Oncogene. 2002; 21: 32-43
- Chronic ethanol causes heterologous desensitization of receptors by reducing ∀S messenger RNA.Nature (London). 1988; 333: 848-850
- Modulation of caspase-3 activity and Fas ligand mRNA expression in rat liver cells in vivo by alcohol and lipopolysaccharide.Alcohol Clin Exp Res. 1999; 23: 349-356
- Inhibition of caspases in vivo protects the rat liver against alcohol-induced sensitization to bacterial lipopolysaccharide.Alcohol Clin Exp Res. 2001; 25: 935-943
- Epidermal growth factor protects the liver against alcohol-induced injury and sensitization to bacterial lipopolysaccharide.Alcohol Clin Exp Res. 2002; 26: 864-874
- Chronic alcohol exposure of rats exacerbates apoptosis in hepatocytes and sinusoidal endothelial cells.Hepatol Res. 2002; 19: 306-324
- Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting N-terminal kinase and caspase-3 activation.J Biol Chem. 2002; 277: 13037-13044
- Apoptosis and Bcl-2 protein expression in experimental alcoholic liver disease in the rat.Alcohol Clin Exp Res. 1995; 19: 854-859
- Ethanol and arachidonic acid increase 2(I) collagen expression in rat hepatic stellate cells overexpressing cytochrome P450 2E1. Role of H2O2 and cyclooxygenase-2.J Biol Chem. 2000; 275: 20136-20145
- Changes in the markers related to collagen synthesis in the liver of chronically alcohol-treated rats.Gastroenterol Jpn. 1992; 27: 54-60
- Increased type I procollagen mRNA levels and in vitro protein synthesis in the baboon model of chronic alcoholic liver disease.Gastroenterology. 1985; 89: 1123-1131
- Alcohol and cytokine networks.Alcohol. 1997; 14: 421-430
- Effect of ethanol and high-fat feeding on hepatic γ-glutamylcysteine synthetase subunit expression in the rat.Hepatology. 1999; 30: 209-214
- Acetaldehyde induces c-fos and c-jun proto-oncogenes in fat storing cells culture through protein kinase C activation.Alcohol Alcohol. 1994; 29: 303-314
- RNA expression in the early characterization of hepatotoxicants in Wistar rats by high-density DNA microarrays.Hepatology. 2002; 33: 1239-1258
- Compound profiling using cDNA array based differential expression of human and rat hepatocytes.Toxicol Sci. 2002; 66 (abstract 45): 9-10
- The use of genomics technology to investigate gene expression changes in cultured human liver cells.Toxicol In Vitro. 2001; 15: 309-405
- Chronic alcohol induced tissue injury: microarray analyses of differential gene regulation.Fed Am Soc Exp Biol J. 2002; 16 (Abstract 16713)
- Identification of differentially expressed genes in hepatocellular carcinoma with cDNA microarrays.Hepatology. 2001; 33: 832-840
- Gene array analysis and the liver.Hepatology. 2002; 36: 1313-1325
- Long-term cannulation model for blood sampling and intragastric infusion in the rat.Am J Physiol. 1984; 247: R595-R599
- Effect of chronic coadministration of endotoxin and ethanol on rat liver pathology and proinflammatory and antiinflammatory cytokines.Hepatology. 1999; 29: 1503-1510
- Single step method of RNA isolation by acid guanidine thiocyanate–phenol–chloroform extraction.Anal Biochem. 1987; 62: 156-161
- Controlling the false discovery rate: a practical and powerful approach to multiple testing.J R Stat Soc Ser B. 1995; 57: 289-300
- Intragastric ethanol infusion model for cellular and molecular studies of alcoholic liver disease.J Biomed Sci. 2001; 8: 20-27
- Role of lipopolysaccharide-binding protein in early alchol-induced liver injury in mice.J Immunol. 2002; 168: 2963-2969
- Essential role of tumor necrosis factor α in EtOH-induced liver injury in mice.Gastroenterology. 1999; 117: 942-952
- Role of cytochromes P450 in drug metabolism and hepatotoxicity.Semin Liv Dis. 1990; 10: 235-250
- Chronic ethanol administration impairs receptor- mediated endocytosis of epidermal growth factor by rat hepatocytes.Hepatology. 1990; 12: 1085-1091
- What factors control hepatic triacylglycerol accumulation in alcohol abuse?.Biochem Soc Trans. 1998; 16: 251-253
- Chronic ethanol increases liver plasma membrane fluidity.Biochemistry. 1985; 24: 3114-3120
- Effects of chronic ethanol feeding on rat hepatocytic glutathione compartmentation, efflux and response to incubation with ethanol.J Clin Invest. 1987; 80: 57-62
- Hepatic mitochondrial glutathione depletion and progression of experimental alcoholic liver disease in rats.Hepatology. 1992; 16: 1423-1427
- Molecular cloning of mouse intestinal trefoil factor and its expression during goblet cell change.Biochem J. 1995; 311: 293-297
- Trefoil peptides as proangiogenic factors in vivo and in vitro: implication of cyclooxygenase-2 and EGF receptor signaling.Fed Am Soc Exp Biol J. 2003; 17: 7-16
- Molecular medicine of TFF-peptides: from gut to brain.Histol Histopathol. 2001; 16: 319-334
- Intestinal endotoxins and macrophages as mediators of liver injury.Trans Am Clin Chem Assoc. 1988; 100: 115-125
- Mechanisms of hepatic toxicity. II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin.Am J Physiol. 1998; 275: G605-G611
- Deoxynucleotide-polymerizing enzymes of calf thymus gland. V. Homogeneous terminal deoxynucleotidyl transferase.J Biol Chem. 1971; 246: 909-916
- Regulation of mammalian melanogenesis I: partial purification and characterization of a dopachrom converting factor: dopachrome tautomerase.Biochim Biophys Acta. 1990; 1035: 266-275
Article info
Publication history
Accepted:
October 16,
2003
Received in revised form:
October 6,
2003
Received:
March 19,
2003
MS 287Identification
Copyright
© 2003 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.