Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis

Raghavakaimal Sreekumar, Barbara Rosado, Deborah Rasmussen, Michael Charlton

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

Although the molecular basis for the pathophysiology of nonalcoholic steatohepatitis (NASH) is poorly understood, insulin resistance and mitochondrial dysfunction are physiologic hallmarks of this condition. We sought evidence of a transcriptional or pretranscriptional basis for insulin resistance and mitochondrial dysfunction through measurement of hepatic gene expression (messenger RNA [mRNA]) using high-density synthetic oligonucleotide microarray analysis (Hu6800 GeneChip, Affymetrix, CA). Global hepatic gene expression was determined in snap-frozen liver biopsy specimens from 4 groups: (1) patients with cirrhotic-stage NASH (n = 6), (2) patients with cirrhosis caused by hepatitis C virus (HCV) (n = 6), (3) patients with cirrhosis secondary to primary biliary cirrhosis (PBC) (n = 6), and (4) healthy controls (n = 6). Genes were considered to be expressed differentially in NASH only if there was a greater than 2-fold difference in abundance of mRNA when compared with each of the control groups. Sixteen genes were uniquely differentially expressed (4 overexpressed and 12 underexpressed) in patients with cirrhotic-stage NASH. Genes that were significantly underexpressed included genes important for maintaining mitochondrial function (copper/zinc superoxide dismutase, aldehyde oxidase, and catalase). Glucose 6-phospatase, alcohol dehydrogenase, elongation factor-TU, methylglutaryl coenzyme A (CoA), acyl CoA synthetase, oxoacyl CoA thiolase, and ubiquitin also were underexpressed in NASH. Genes that were overexpressed in NASH included complement component C3 and hepatocyte-derived fibrinogen-related protein, potentially contributing to impaired insulin sensitivity. In conclusion, these studies provide evidence for a transcriptional or pretranscriptional basis for impaired mitochondrial function (attenuated capacity for the dismutation of reactive oxygen species) and diminished insulin sensitivity (increased acute phase reactants) in patients with histologically progressive NASH. Further studies are required to determine the mechanism and the physiologic significance of these findings.

Original languageEnglish (US)
Pages (from-to)244-251
Number of pages8
JournalHepatology
Volume38
Issue number1
DOIs
StatePublished - Jul 1 2003

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Gene Expression
Liver
Insulin Resistance
Genes
Coenzyme A
Fibrosis
Aldehyde Oxidase
Coenzyme A Ligases
Peptide Elongation Factors
Messenger RNA
Complement C3
Biliary Liver Cirrhosis
Acute-Phase Proteins
Alcohol Dehydrogenase
Microarray Analysis
Ubiquitin
Non-alcoholic Fatty Liver Disease
Oligonucleotide Array Sequence Analysis
Hepacivirus
Catalase

ASJC Scopus subject areas

  • Hepatology

Cite this

Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis. / Sreekumar, Raghavakaimal; Rosado, Barbara; Rasmussen, Deborah; Charlton, Michael.

In: Hepatology, Vol. 38, No. 1, 01.07.2003, p. 244-251.

Research output: Contribution to journalArticle

Sreekumar, R, Rosado, B, Rasmussen, D & Charlton, M 2003, 'Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis', Hepatology, vol. 38, no. 1, pp. 244-251. https://doi.org/10.1053/jhep.2003.50290
Sreekumar, Raghavakaimal ; Rosado, Barbara ; Rasmussen, Deborah ; Charlton, Michael. / Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis. In: Hepatology. 2003 ; Vol. 38, No. 1. pp. 244-251.
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