Regulation of mevalonate synthesis in low density lipoprotein receptor knockout mice fed n-3 or n-6 polyunsaturated fatty acids.
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 knock-out or transgenic animals.
El-Sohemy
A
A
Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Canada.
Archer
M C
MC
D000818:Animals; D004032:Diet; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage*; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics
D005231:Fatty Acids, Unsaturated; D011973:Receptors, LDL; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid