Functional diversity of apolipoprotein E: from subcellular localization to mitochondrial function

Abstract

Human apolipoprotein E (APOE), originally known for its role in lipid metabolism, is polymorphic with three major allele forms, namely, APOEε2, APOEε3, and APOEε4, leading to three different human APOE isoforms. The ε4 allele is a genetic risk factor for Alzheimer’s disease (AD); therefore, the vast majority of APOE research focuses on its role in AD pathology. However, there is increasing evidence for other functions of APOE through the involvement in other biological processes such as transcriptional regulation, mitochondrial metabolism, immune response, and responsiveness to dietary factors. Therefore, the aim of this review is to provide an overview of the potential novel functions of APOE and their characterization. The detection of APOE in various cell organelles points to previously unrecognized roles in mitochondria and others, although it is actually considered a secretory protein. Furthermore, numerous interactions of APOE with other proteins have been detected, providing indications for new metabolic pathways involving APOE. The present review summarizes the current evidence on APOE beyond its original role in lipid metabolism, to change the perspective and encourage novel approaches to future research on APOE and its isoform-dependent role in the cellular metabolism.

Human APOE4 Protects High-Fat and High-Sucrose Diet Fed Targeted Replacement Mice against Fatty Liver Disease Compared to APOE3

“…Since the etiology of those disorders is complex involving multiple different biochemical and histological hallmarks, a comprehensive explanation of this supposed contradiction seems almost impossible. At least, it may be of significance to note that APOE has been emphasized to exhibit differential cellular effects in the brain as opposed to the liver [ 103 ]. For example, while brain ATP levels are actually lower in APOE4 than APOE3 expressing mice [ 50 ], no differences have been observed in the liver [ 56 ].…”

The mitochondrial BCKD complex interacts with hepatic apolipoprotein E in cultured cells in vitro and mouse livers in vivo

“…Nothing is known about a potential mitochondrial translocation mechanism for APOE so far, although several studies have already shown the localization of the APOE protein in mitochondria [52][53][54]. A detailed review on mitochondrial localization and function of APOE is given in our review (Rueter et al [55]).…”

Apolipoprotein E (APOE) Haplotypes in Healthy Subjects from Worldwide Macroareas: A Population Genetics Perspective for Cardiovascular Disease, Neurodegeneration, and Dementia

“…Extensive genetic studies on these isoforms also associate APOE isoforms with well-being and longevity [ 13 ]: individuals with the ε3 allele gain more energy from food and body fat deposits, while subjects carrying ε4 undergo rapid fatty acid mobilization associated with a high-fat diet in colder climates [ 14 , 15 ]. Indeed, it is well known that APOE is a pleiotropic gene, its protein isoforms have different functions in several expression contexts, as well as that the environment is crucial for the manifestation of a pathological condition [ 16 , 17 ]. However, there are few studies trying to observe this gene beyond the three classic isoforms and the simple effect of single point mutations across its length in the context of cardiovascular and neurological diseased states [ 18 , 19 ].…”