Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis

被引:149
作者
Sreekumar, R [1 ]
Rosado, B [1 ]
Rasmussen, D [1 ]
Charlton, M [1 ]
机构
[1] Mayo Clin & Mayo Fdn, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA
关键词
D O I
10.1053/jhep.2003.50290
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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 prctranscriptional 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 dehydrogcnase, 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.
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页码:244 / 251
页数:8
相关论文
共 56 条
[1]   Insulin's effect on synthesis rates of liver proteins - A swine model comparing various precursors of protein synthesis [J].
Ahlman, B ;
Charlton, M ;
Fu, AZ ;
Berg, C ;
O'Brien, P ;
Nair, KS .
DIABETES, 2001, 50 (05) :947-954
[2]   Age effect on transcript levels and synthesis rate of muscle MHC and response to resistance exercise [J].
Balagopal, P ;
Schimke, JC ;
Ades, P ;
Adey, D ;
Nair, KS .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2001, 280 (02) :E203-E208
[3]  
BONDY SC, 1994, ALCOHOL ALCOHOLISM, V29, P375
[4]   Apolipoprotein synthesis in nonalcoholic steatohepatitis [J].
Charlton, N ;
Sreekumar, R ;
Rasmussen, D ;
Lindor, K ;
Nair, KS .
HEPATOLOGY, 2002, 35 (04) :898-904
[5]   MEASUREMENT OF CATALASE ACTIVITY IN TISSUE EXTRACTS [J].
COHEN, G ;
DEMBIEC, D ;
MARCUS, J .
ANALYTICAL BIOCHEMISTRY, 1970, 34 (01) :30-+
[6]   Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis - A pilot study [J].
Cortez-Pinto, H ;
Chatham, J ;
Chacko, VP ;
Arnold, C ;
Rashid, A ;
Diehl, AM .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1999, 282 (17) :1659-1664
[7]  
CRYER DR, 1986, J LIPID RES, V27, P508
[8]   RATE-LIMITING FUNCTION OF 3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A SYNTHASE IN KETOGENESIS [J].
DASHTI, N ;
ONTKO, JA .
BIOCHEMICAL MEDICINE, 1979, 22 (03) :365-374
[9]   Plant gene expression response to Agrobacterium tumefaciens [J].
Ditt, RF ;
Nester, EW ;
Comai, L .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (19) :10954-10959
[10]   Overweight and obesity in the United States: prevalence and trends, 1960-1994 [J].
Flegal, KM ;
Carroll, MD ;
Kuczmarski, RJ ;
Johnson, CL .
INTERNATIONAL JOURNAL OF OBESITY, 1998, 22 (01) :39-47