title: Human apolipoprotein E allele and docosahexaenoic acid intake modulate peripheral cholesterol homeostasis in mice.
abstract: Carrying at least one apolipoprotein E ε4 allele (E4+) is the main genetic risk factor for Alzheimer's disease (AD). Epidemiological studies support that consuming fatty fish rich in docosahexaenoic acid (DHA; 22:6ω3) is protective against development of AD. However, this protective effect seems not to hold in E4+. The involvement of APOE genotype on the relationship between DHA intake and cognitive decline could be mediated through cholesterol. Many studies show a link between cholesterol metabolism and AD progression. In this study, we investigated whether cholesterol metabolism is improved in E3+ and E4+ mice consuming a diet rich in DHA. Plasma cholesterol was 36% lower in E4+ mice compared to E3+ mice fed the control diet (P=.02), and in the liver, there was a significant genotype effect where cholesterol levels were 18% lower in E4+ mice than E3+ mice. The low-density lipoprotein receptor was overexpressed in the liver of E4+ mice. Plasma cholesterol levels were 33% lower after the DHA diet (P=.02) in E3+ mice only, and there was a significant diet effect where cholesterol level was 67% lower in the liver of mice fed DHA. Mice fed the DHA diet also had 62% less lipolysis stimulated lipoprotein receptor expression in the liver compared to mice fed the control diet (P<.0001), but there was no genotype effect. These findings suggest that plasma and liver cholesterol homeostasis and the receptors regulating uptake of cholesterol in the liver are modulated differently and independently by APOE allele and DHA intake.
authors.affiliation: Research Center on Aging, Department of Physiology, Université de Sherbrooke, 1036 Belvédère Sud, Sherbrooke, Québec, Canada, J1H 4C4; Institute of Nutrition and Functional Foods, 2440 Boulevard Hochelaga, Québec City, Québec, Canada, G1V 0A6.
authors.forename: Anthony
authors.initials: A
authors.lastname: Pinçon
authors.affiliation: Research Center on Aging, Department of Physiology, Université de Sherbrooke, 1036 Belvédère Sud, Sherbrooke, Québec, Canada, J1H 4C4; Institute of Nutrition and Functional Foods, 2440 Boulevard Hochelaga, Québec City, Québec, Canada, G1V 0A6.
authors.forename: Jean-Denis
authors.initials: JD
authors.lastname: Coulombe
authors.affiliation: Research Center on Aging, Department of Physiology, Université de Sherbrooke, 1036 Belvédère Sud, Sherbrooke, Québec, Canada, J1H 4C4; Institute of Nutrition and Functional Foods, 2440 Boulevard Hochelaga, Québec City, Québec, Canada, G1V 0A6.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Chouinard-Watkins
authors.affiliation: Research Center on Aging, Department of Physiology, Université de Sherbrooke, 1036 Belvédère Sud, Sherbrooke, Québec, Canada, J1H 4C4; Institute of Nutrition and Functional Foods, 2440 Boulevard Hochelaga, Québec City, Québec, Canada, G1V 0A6; Department of Medicine, Université de Sherbrooke, 2500 Boul. de l'Université, Sherbrooke, Québec, Canada, J1K 2R1. Electronic address: Melanie.plourde2@usherbrooke.ca.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Plourde
mesh_terms: D000483:Alleles; D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D053318:Apolipoprotein E3 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D008066:Lipolysis; D008099:Liver / Q000378:metabolism*; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D014886:Weaning
chemical_list: D000924:Anticholesteremic Agents; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D011973:Receptors, LDL; C085992:lipolysis-stimulated receptor; D004281:Docosahexaenoic Acids; D002784:Cholesterol
keywords: Apolipoprotein E; Cholesterol; Diet; Docosahexaenoic acid; Metabolism; Mice