title: Influence of the APOE genotype on hepatic stress response: Studies in APOE targeted replacement mice and human liver cells.
abstract: Apolipoprotein E (APOE) is a multifunctional plasma protein mainly acting in lipid metabolism. Human APOE is polymorphic with three major isoforms (APOE2, APOE3 and APOE4). Up to 75% of the body's APOE is produced by the liver. There is increasing evidence from studies in brain-derived cells that APOE4 affects mitochondrial function and biogenesis as well as stress and inflammatory responses - processes, whose disturbances are considered hallmarks of the ageing process. However, although the liver is the main production site of APOE, knowledge about the impact of the APOE genotype on hepatic stress response-related processes is rather limited. Therefore, we studied biomarkers of oxidative status (glutathione levels, 3-nitrotyrosine adducts, protein carbonyl concentration), ER stress (XBP1(S), BiP, DDIT3), proteasome activity, mitochondrial function (respiratory complexes, ATP levels and mitochondrial membrane potential as well as biomarkers of mitochondrial biogenesis, fission and fusion), autophagy (LC3, LAMP2A), apoptosis (BCL2, BAX, CYCS) and DNA damage in the liver of APOE targeted replacement (TR) mice and in Huh7 hepatocytes overexpressing the APOE3 and the APOE4 isoform, respectively. APOE4 mice exhibited a lower chymotrypsin-like and a higher trypsin-like proteasome activity. Levels of protein carbonyls were moderately higher in liver tissue of APOE4 vs. APOE3 mice. Other biomarkers of oxidative stress were similar between the two genotypes. Under basal conditions, the stress-response pathways investigated appeared largely unaffected by the APOE genotype. However, upon stress induction, APOE4 expressing cells showed lower levels of adenosine triphosphate (ATP) and lower mRNA levels of the ATP-generating complex V of the mitochondrial respiratory chain. Overall, our findings provide evidence for a rather low influence of the APOE genotype on the hepatic stress response processes investigated in this study.
authors.affiliation: Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Str. 6, 24118 Kiel, Germany. Electronic address: dose@foodsci.uni-kiel.de.
authors.forename: Janina
authors.initials: J
authors.lastname: Dose
authors.affiliation: Institute of Clinical Molecular Biology, University of Kiel, University Hospital Schleswig-Holstein, Schittenhelmstr. 12, 24105 Kiel, Germany. Electronic address: a.nebel@mucosa.de.
authors.forename: Almut
authors.initials: A
authors.lastname: Nebel
authors.affiliation: Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Str. 6, 24118 Kiel, Germany. Electronic address: piegholdt@foodsci.uni-kiel.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Piegholdt
authors.affiliation: Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Str. 6, 24118 Kiel, Germany. Electronic address: rimbach@foodsci.uni-kiel.de.
authors.forename: Gerald
authors.initials: G
authors.lastname: Rimbach
authors.affiliation: Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Str. 6, 24118 Kiel, Germany. Electronic address: huebbe@foodsci.uni-kiel.de.
authors.forename: Patricia
authors.initials: P
authors.lastname: Huebbe
mesh_terms: D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics*; D053318:Apolipoprotein E3 / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics*
chemical_list: D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D015415:Biomarkers; D020033:Protein Isoforms
keywords: ATP; Apolipoprotein E isoform; Apoptosis; Autophagy; Endoplasmic reticulum stress; Hepatocytes; Mitochondrial function; Proteasome activity