Influence of the APOE genotype on hepatic stress response: Studies in APOE targeted replacement mice and human liver cells

Dose, J., Nebel, A., Piegholdt, S., Rimbach, Gerald and Huebbe, P. (2016) Influence of the APOE genotype on hepatic stress response: Studies in APOE targeted replacement mice and human liver cells Free Radical Biology and Medicine, 96 . pp. 264-272. DOI 10.1016/j.freeradbiomed.2016.04.031.

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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 mitochondria) 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. (C) 2016 Elsevier Inc. All rights reserved.

Document Type: Article
Additional Information: Times Cited: 0 Dose, Janina Nebel, Almut Piegholdt, Stefanie Rimbach, Gerald Huebbe, Patricia
Research affiliation: Kiel University
OceanRep > The Future Ocean - Cluster of Excellence
Refereed: Yes
DOI etc.: 10.1016/j.freeradbiomed.2016.04.031
ISSN: 0891-5849
Projects: Future Ocean
Date Deposited: 07 Mar 2017 10:41
Last Modified: 07 Mar 2017 10:41
URI: http://eprints.uni-kiel.de/id/eprint/36063

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