Regulation by hypoxia of methionine adenosyltransferase activity and gene expression in rat hepatocytes

被引:82
作者
Avila, MA [1 ]
Carretero, MV [1 ]
Rodriguez, EN [1 ]
Mato, JM [1 ]
机构
[1] CSIC, Inst Invest Biomed, Madrid, Spain
关键词
D O I
10.1016/S0016-5085(98)70489-5
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: Oxygen supply to the hepatic parenchyma is compromised by long-or short-term ethanol consumption and pathological conditions such as cirrhosis. Impairment in the production of S-adenosyl-L-methionine, the major methylating agent, occurs during hypoxia. In this study, the molecular mechanisms implicated in the regulation of S-adenosyl-L-methionine synthesis by oxygen levels were investigated. Methods: Rat hepatocytes were isolated and cultured under normoxic (21% O-2) or hypoxic (3% O-2) conditions for different periods. Methionine adenosyltransferase activity, messenger RNA levels, and nuclear transcription were evaluated. Results: Methionine adenosyltransferase was inactivated in hepatocytes kept under low oxygen levels. Hypoxia induced the expression of nitric oxide (NO) synthase, and the inactivation of methionine adenosyltransferase was prevented by the NO synthase inhibitor N-G-monomethyl-L-arginine methyl ester. Methionine adenosyltransferase messenger RNA levels were down-regulated by hypoxia, through a mechanism that might involve a hemoprotein. Hypoxia dramatically reduced methionine adenosyltransferase gene transcription, and messenger stability was also decreased, although to a lesser extent. Conclusions: We have established the molecular basis for the regulation of methionine adenosyltransferase activity and gene expression by hypoxia. NO-mediated inactivation and transcriptional arrest seem to be the two major pathways by which oxygen levels control hepatic methionine adenosyltransferase, the enzyme necessary for methylation reactions and for the synthesis of polyamines and glutathione.
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页码:364 / 371
页数:8
相关论文
共 44 条
[1]   ANALYSIS OF THE 5' NONCODING REGION OF RAT-LIVER S-ADENOSYLMETHIONINE SYNTHETASE MESSENGER-RNA AND COMPARISON OF THE MR DEDUCED FROM THE CDNA SEQUENCE AND THE PURIFIED ENZYME [J].
ALVAREZ, L ;
ASUNCION, M ;
CORRALES, F ;
PAJARES, MA ;
MATO, JM .
FEBS LETTERS, 1991, 290 (1-2) :142-146
[2]   INSULIN-LIKE EFFECTS OF INOSITOL PHOSPHATE-GLYCAN ON MESSENGER-RNA EXPRESSION IN RAT HEPATOCYTES [J].
ALVAREZ, L ;
AVILA, MA ;
MATO, JM ;
CASTANO, JG ;
VARELANIETO, I .
MOLECULAR ENDOCRINOLOGY, 1991, 5 (08) :1062-1068
[3]  
ARTEEL GE, 1997, AM J PHYSIOL, V271, pG494
[4]  
Avila MA, 1997, HEPATOLOGY, V25, P391
[5]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[6]   Oxygen sensing and molecular adaptation to hypoxia [J].
Bunn, HF ;
Poyton, RO .
PHYSIOLOGICAL REVIEWS, 1996, 76 (03) :839-885
[7]   SPECIFIC LOSS OF THE HIGH-MOLECULAR-WEIGHT FORM OF S-ADENOSYL-L-METHIONINE SYNTHETASE IN HUMAN-LIVER CIRRHOSIS [J].
CABRERO, C ;
DUCE, AM ;
ORTIZ, P ;
ALEMANY, S ;
MATO, JM .
HEPATOLOGY, 1988, 8 (06) :1530-1534
[8]   BIOLOGICAL METHYLATION - SELECTED ASPECTS [J].
CANTONI, GL .
ANNUAL REVIEW OF BIOCHEMISTRY, 1975, 44 :435-451
[9]   REOXYGENATION INJURY IN ISOLATED RAT HEPATOCYTES - RELATION TO OXYGEN-FREE RADICALS AND LIPID-PEROXIDATION [J].
CARACENI, P ;
ROSENBLUM, ER ;
VANTHIEL, DH ;
BORLE, AB .
AMERICAN JOURNAL OF PHYSIOLOGY, 1994, 266 (05) :G799-G806
[10]  
Chawla RK, 1996, J CELL BIOCHEM, V61, P72