ORIGINAL ARTICLE Nrf2-dependent gene expression is affected by the proatherogenic apoE4 genotype—studies in targeted gene replacement mice Anne-Christin Graeser & Christine Boesch-Saadatmandi & Jana Lippmann & Anika E. Wagner & Patricia Huebbe & Niels Storm & Wolfgang Höppner & Ingrid Wiswedel & Andreas Gardemann & Anne M. Minihane & Frank Döring & Gerald Rimbach Received: 26 January 2011 /Revised: 31 March 2011 /Accepted: 9 May 2011 /Published online: 28 May 2011 # Springer-Verlag 2011 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 preven- tion 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 dehydro- genase, 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. Keywords Cardiovascular disease . Nrf2 . ApoE . Glutathione-S-transferase . Heme oxygenase-1 . MicroRNA . Mice Introduction Apolipoprotein E (apoE) plays a central role in cardiovas- cular homeostasis and is a recognized mediator of many metabolic processes underlying atherogenesis. The 34-kDa protein, mainly produced in the liver, is involved in hepatic lipoprotein secretion and lipoprotein metabolism in the circulation, and serves as a high affinity ligand for cellular lipoprotein uptake. Furthermore, apoE exhibits important functions in macrophage metabolism playing a central role in cholesterol efflux [1] and acting as a potential modulator of the macrophage mediated inflammatory response. Three common isoforms of the apoE protein exist in humans namely apoE2, apoE3, and apoE4. ApoE3 is the A.-C. Graeser : C. Boesch-Saadatmandi : J. Lippmann : A. E. Wagner : P. Huebbe : G. Rimbach (*) Institute of Human Nutrition and Food Science, Department of Food Science, Christian-Albrechts-University Kiel, Hermann-Rodewald-Strasse 6, 24118 Kiel, Germany e-mail: rimbach@foodsci.uni-kiel.de N. Storm : W. Höppner Bioglobe GmbH, Grandweg 64, 22529 Hamburg, Germany I. Wiswedel : A. Gardemann Department of Pathological Biochemistry, Medical Faculty, Otto-von-Guericke-University, Leipziger Str. 44, 39120 Magdeburg, Germany A. M. Minihane School of Medicine, University of East Anglia, Norwich NR4 7TJ, UK F. Döring Department of Molecular Prevention, Institute of Human Nutrition and Food Science, Christian-Albrechts-University Kiel, Heinrich-Hecht-Platz 10, 24118 Kiel, Germany J Mol Med (2011) 89:1027–1035 DOI 10.1007/s00109-011-0771-1