title: Nrf2-dependent gene expression is affected by the proatherogenic apoE4 genotype-studies in targeted gene replacement mice.
abstract: An apoE4 genotype is an important risk factor for cardiovascular and other chronic diseases. The higher cardiovascular disease risk of apoE4 carriers as compared to the apoE3 genotype has been mainly attributed to the differences in blood lipids between the two genotype subgroups. Recently, a potential protective role of the transcription factor Nrf2 in cardiovascular disease prevention has been suggested. In this study, we show that Nrf2-dependent gene expression is affected by the apoE genotype. ApoE4 vs. apoE3 mice exhibited lower hepatic Nrf2 nuclear protein levels. Furthermore, mRNA and protein levels of Nrf2 target genes including glutathione-S-transferase, heme oxygenase-1 and NAD(P)H dehydrogenase, quinone 1 were significantly lower in apoE4 as compared to apoE3 mice. Lower hepatic mRNA levels of phase II enzymes, as observed in apoE4 vs. apoE3 mice, were accompanied by higher mRNA levels of phase I enzymes including Cyp26a1 and Cyp3a16. Furthermore, miRNA-144, miRNA-125b, and miRNA-29a involved in Nrf2 signaling, inflammation, and regulation of phase I enzyme gene expression were affected by the apoE genotype. We provide first evidence that Nrf2 is differentially regulated in response to the apoE genotype.
authors.affiliation: Institute of Human Nutrition and Food Science, Department of Food Science, Christian-Albrechts-University Kiel, Hermann-Rodewald-Strasse 6, 24118, Kiel, Germany.
authors.forename: Anne-Christin
authors.initials: AC
authors.lastname: Graeser
authors.forename: Christine
authors.initials: C
authors.lastname: Boesch-Saadatmandi
authors.forename: Jana
authors.initials: J
authors.lastname: Lippmann
authors.forename: Anika E
authors.initials: AE
authors.lastname: Wagner
authors.forename: Patricia
authors.initials: P
authors.lastname: Huebbe
authors.forename: Niels
authors.initials: N
authors.lastname: Storm
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Höppner
authors.forename: Ingrid
authors.initials: I
authors.lastname: Wiswedel
authors.forename: Andreas
authors.initials: A
authors.lastname: Gardemann
authors.forename: Anne M
authors.initials: AM
authors.lastname: Minihane
authors.forename: Frank
authors.initials: F
authors.lastname: Döring
authors.forename: Gerald
authors.initials: G
authors.lastname: Rimbach
mesh_terms: D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D019295:Computational Biology; D019175:DNA Methylation / Q000235:genetics; D028441:F2-Isoprostanes / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018390:Gene Targeting; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D053327:Apolipoprotein E4; D028441:F2-Isoprostanes; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone; D002784:Cholesterol; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D005982:Glutathione Transferase