Genetic and dietary interactions in the regulation of HMG-CoA reductase gene expression.
Base-Sequence, Cholesterol, Cholesterol-Dietary, Cholestyramine, Circadian-Rhythm, Dietary-Fats, Female, Gene-Expression-Regulation-Enzymologic, Hydroxymethylglutaryl-CoA-Reductases: ge, me, Lipids, Liver: en, Lovastatin, Mice, Mice-Inbred-Strains, Molecular-Sequence-Data, Organ-Specificity, Promoter-Regions-(Genetics), Restriction-Fragment-Length-Polymorphisms, RNA-Messenger: ge, me, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, Variation-(Genetics)
J Lipid Res 1992 May;33(5):711-25
HL30568, HL42488, GM18684
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.
Hwa, J J.; Zollman, S; Warden, C H.; Taylor, B A.; Edwards, P A.; Fogelman, A M.; and Lusis, A J., " Genetic and dietary interactions in the regulation of HMG-CoA reductase gene expression." (1992). Faculty Research 1990 - 1999. 264.