Genetic and dietary interactions in the regulation of HMG-CoA reductase gene expression.
Inbred strains of mice exhibit large genetic variations in hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity. A tissue-specific genetic variation between the strains BALB/c and C57BL/6, resulting in about 5-fold higher levels in hepatic reductase activity in strain C57BL/6,...
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1992-05-01
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doaj-880dbab9f3f041b1b4c125667912c6222021-04-26T05:52:36ZengElsevierJournal of Lipid Research0022-22751992-05-01335711725Genetic and dietary interactions in the regulation of HMG-CoA reductase gene expression.JJ Hwa0S Zollman1CH Warden2BA Taylor3PA Edwards4AM Fogelman5AJ Lusis6Department of Medicine, University of California, Los Angeles 90024.Department of Medicine, University of California, Los Angeles 90024.Department of Medicine, University of California, Los Angeles 90024.Department of Medicine, University of California, Los Angeles 90024.Department of Medicine, University of California, Los Angeles 90024.Department of Medicine, University of California, Los Angeles 90024.Department of Medicine, University of California, Los Angeles 90024.Inbred strains of mice exhibit large genetic variations in hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity. A tissue-specific genetic variation between the strains BALB/c and C57BL/6, resulting in about 5-fold higher levels in hepatic reductase activity in strain C57BL/6, was examined in detail. The activity difference between these two strains could be explained entirely by differences in hepatic reductase mRNA levels. In genetic crosses, the variation segregated as a single major Mendelian element. Surprisingly, the mode of inheritance was recessive since F1 mice exhibited the BALB/c levels of enzyme activity. Despite the fact that the rates of hepatic sterol synthesis also differed between the strains by a factor of about five, the altered hepatic reductase expression did not significantly influence plasma lipoprotein levels. The response to a high cholesterol, high fat diet between the strains was remarkably different. Thus, in BALB/c mice, both hepatic reductase activity and mRNA levels were affected only slightly, if at all, by cholesterol feeding, while in strain C57BL/6 mice both were reduced more than 10-fold by cholesterol feeding. Several lines of evidence, including analysis of cis-acting regulatory elements, the nonadditive mode of inheritance, and genetic studies of the HMG-CoA reductase gene locus on mouse chromosome 13, support the possibility that the variation in reductase expression is not due to a mutation of the structural gene but, rather, is determined by a trans-acting factor controlling reductase mRNA levels. The variation provides a striking example, at the molecular level, of the importance of dietary-genetic interactions in the control of cholesterol metabolism.http://www.sciencedirect.com/science/article/pii/S002222752041435X |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
JJ Hwa S Zollman CH Warden BA Taylor PA Edwards AM Fogelman AJ Lusis |
spellingShingle |
JJ Hwa S Zollman CH Warden BA Taylor PA Edwards AM Fogelman AJ Lusis Genetic and dietary interactions in the regulation of HMG-CoA reductase gene expression. Journal of Lipid Research |
author_facet |
JJ Hwa S Zollman CH Warden BA Taylor PA Edwards AM Fogelman AJ Lusis |
author_sort |
JJ Hwa |
title |
Genetic and dietary interactions in the regulation of HMG-CoA reductase gene expression. |
title_short |
Genetic and dietary interactions in the regulation of HMG-CoA reductase gene expression. |
title_full |
Genetic and dietary interactions in the regulation of HMG-CoA reductase gene expression. |
title_fullStr |
Genetic and dietary interactions in the regulation of HMG-CoA reductase gene expression. |
title_full_unstemmed |
Genetic and dietary interactions in the regulation of HMG-CoA reductase gene expression. |
title_sort |
genetic and dietary interactions in the regulation of hmg-coa reductase gene expression. |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
1992-05-01 |
description |
Inbred strains of mice exhibit large genetic variations in hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity. A tissue-specific genetic variation between the strains BALB/c and C57BL/6, resulting in about 5-fold higher levels in hepatic reductase activity in strain C57BL/6, was examined in detail. The activity difference between these two strains could be explained entirely by differences in hepatic reductase mRNA levels. In genetic crosses, the variation segregated as a single major Mendelian element. Surprisingly, the mode of inheritance was recessive since F1 mice exhibited the BALB/c levels of enzyme activity. Despite the fact that the rates of hepatic sterol synthesis also differed between the strains by a factor of about five, the altered hepatic reductase expression did not significantly influence plasma lipoprotein levels. The response to a high cholesterol, high fat diet between the strains was remarkably different. Thus, in BALB/c mice, both hepatic reductase activity and mRNA levels were affected only slightly, if at all, by cholesterol feeding, while in strain C57BL/6 mice both were reduced more than 10-fold by cholesterol feeding. Several lines of evidence, including analysis of cis-acting regulatory elements, the nonadditive mode of inheritance, and genetic studies of the HMG-CoA reductase gene locus on mouse chromosome 13, support the possibility that the variation in reductase expression is not due to a mutation of the structural gene but, rather, is determined by a trans-acting factor controlling reductase mRNA levels. The variation provides a striking example, at the molecular level, of the importance of dietary-genetic interactions in the control of cholesterol metabolism. |
url |
http://www.sciencedirect.com/science/article/pii/S002222752041435X |
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