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Regulation of mevalonate synthesis in low density lipoprotein receptor knockout mice fed n-3 or n-6 polyunsaturated fatty acids

  • Published:
Lipids

Abstract

3-Hydroxy-3-methylglutaryl (HMG)-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, catalyzes the formation of mevalonate which is also required for cell proliferation. Changes in HMG-CoA reductase may mediate the differential effects of n-3 and n-6 polyunsaturated fatty acids (PUFA) on experimental mammary tumorigenesis, but the mechanisms by which these fatty acids regulate HMG-CoA reductase are unclear. To determine whether the low density lipoprotein receptor (LDL-R) is required for this regulation, groups of female LDL-R knockout (−/−) and wild-type (+/+) mice were fed 7% fat diets rich in either n-3 (menhaden oil) or n-6 (safflower oil) PUFA for 1 wk. Dietary PUFA and deletion of the LDL-R had independent effects on HMG-CoA reductase and serum lipids, and a significant diet-gene interaction was observed. The effects of PUFA on HMG-CoA reductase in the mammary gland, but not the liver, were mediated by the LDL-R. We also observed that differences in HMG-CoA reductase and serum LDL-cholesterol, high density lipoprotein cholesterol, and triglycerides between −/− and +/+ mice were dependent on whether the mice were fed n-3 or n-6 PUFA. Differences between −/− and +/+ mice were much greater when animals were fed n-6 PUFA rather than n-3 PUFA. These results show that the LDL-R mediates the effects of PUFA on HMG-CoA reductase in the mammary gland but not the liver. Furthermore, the composition of dietary PUFA profoundly influences the effects of deleting the LDL-R on HMG-CoA reductase and serum lipids and suggests that diet may influence the phenotype of other knockout or transgenic animals.

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Abbreviations

ANOVA:

analysis of variance

HDL:

high density lipoprotein

HMG:

3-hydroxy-3-methylglutaryl

PUFA:

polyunsaturated fatty acid(s)

LDL:

low density lipoprotein

LDL-R:

LDL receptor

+/+:

wild-type

−/−:

khockout

SDS-PAGE:

sodium dodecylsulfate-polyacrylamide gel electrophoresis

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Authors and Affiliations

  1. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, 150 College St., M5S 3E2, Toronto, Canada

    Ahmed El-Sohemy & Michael C. Archer

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  1. Ahmed El-Sohemy
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  2. Michael C. Archer
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Correspondence to Michael C. Archer.

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El-Sohemy, A., Archer, M.C. Regulation of mevalonate synthesis in low density lipoprotein receptor knockout mice fed n-3 or n-6 polyunsaturated fatty acids. Lipids 34, 1037–1043 (1999). https://doi.org/10.1007/s11745-999-0455-8

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  • DOI: https://doi.org/10.1007/s11745-999-0455-8

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