Genetic and dietary interactions in the regulation of HMG-CoA reductase gene expression

J. J. Hwa, S. Zollman, Craig H Warden, B. A. Taylor, P. A. Edwards, A. M. Fogelman, A. J. Lusis

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)711-725
Number of pages15
JournalJournal of Lipid Research
Volume33
Issue number5
StatePublished - 1992

Keywords

  • cholesterol metabolism
  • high cholesterol diet
  • high fat diet
  • inbred strains of mice
  • lipoproteins

ASJC Scopus subject areas

  • Endocrinology

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