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 a lso required for cell proliferation. Changes in HMG-CoA reductase may media te the differential effects of n-3 and n-6 polyunsaturated fatty acids (PUF A) on experimental mammary tumorigenesis, but the mechanisms by which these fatty acids regulate HMG-CoA reductase are unclear. To determine whether t he 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 f or 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 glan d, but not the liver, were mediated by the LDL-R. We also observed that dif ferences in HMG-CoA reductase and serum LDL-cholesterol, high density lipop rotein cholesterol, and triglycerides between -/- and +/+ mice were depende nt on whether the mice were fed n-3 or n-6 PUFA. Differences between -/- an d +/+ 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 HM G-CoA reductase in the mammary gland but not the liver. Furthermore, the co mposition of dietary PUFA profoundly influences the effects of deleting the LDL-R on HMG-CoA reductase and serum lipids and suggests that diet may inf luence the phenotype of other knockout or transgenic animals.