In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 10 ( 2001-05-08), p. 5560-5565
Abstract:
Liver-specific and nonliver-specific methionine
adenosyltransferases (MATs) are products of two genes, MAT1A and MAT2A , respectively, that
catalyze the formation of S -adenosylmethionine (AdoMet),
the principal biological methyl donor. Mature liver expresses MAT1A , whereas MAT2A is expressed in
extrahepatic tissues and is induced during liver growth and dedifferentiation. To examine the influence of MAT1A on
hepatic growth, we studied the effects of a targeted disruption of the murine MAT1A gene. MAT1A mRNA and protein
levels were absent in homozygous knockout mice. At 3 months, plasma methionine level increased 776% in knockouts. Hepatic AdoMet and
glutathione levels were reduced by 74 and 40%, respectively, whereas S -adenosylhomocysteine, methylthioadenosine, and global
DNA methylation were unchanged. The body weight of 3-month-old knockout mice was unchanged from wild-type littermates, but the liver weight was
increased 40%. The Affymetrix genechip system and Northern
and Western blot analyses were used to analyze differential expression of genes. The expression of many acute phase-response and inflammatory
markers, including orosomucoid, amyloid, metallothionein, Fas antigen, and growth-related genes, including early growth response 1
and proliferating cell nuclear antigen, is increased in the knockout animal. At 3 months, knockout mice are more susceptible to
choline-deficient diet-induced fatty liver. At 8 months, knockout mice developed spontaneous macrovesicular steatosis and predominantly
periportal mononuclear cell infiltration. Thus, absence of MAT1A resulted in a liver that is more susceptible to
injury, expresses markers of an acute phase response, and displays increased proliferation.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.091016398
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2001
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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