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Regulation of mevalonate synthesis in low density lipoprotein receptor knockout mice fed n‐3 or n‐6 polyunsaturated fatty acids
Author(s) -
ElSohemy Ahmed,
Archer Michael C.
Publication year - 1999
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/s11745-999-0455-8
Subject(s) - lipidology , clinical chemistry , polyunsaturated fatty acid , knockout mouse , ldl receptor , chemistry , biochemistry , receptor , cholesterol , sterol regulatory element binding protein , medicine , endocrinology , biology , microbiology and biotechnology , lipoprotein , fatty acid , sterol
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.