APOE genotype and stress response - a mini review

Abstract

The APOE gene is one of currently only two genes that have consistently been associated with longevity. Apolipoprotein E (APOE) is a plasma protein which plays an important role in lipid and lipoprotein metabolism. In humans, there are three major APOE isoforms, designated APOE2, APOE3, and APOE4. Of these three isoforms, APOE3 is most common while APOE4 was shown to be associated with age-related diseases, including cardiovascular and Alzheimer's disease, and therefore an increased mortality risk with advanced age. Evidence accumulates, showing that oxidative stress and, correspondingly, mitochondrial function is affected in an APOE isoform-dependent manner. Accordingly, several stress response pathways implicated in the aging process, including the endoplasmic reticulum stress response and immune function, appear to be influenced by the APOE genotype. The investigation and development of treatment strategies targeting APOE4 have not resolved any therapeutic yet that could be entirely recommended. This mini-review provides an overview on the state of research concerning the impact of the APOE genotype on stress response-related processes, emphasizing the strong interconnection between mitochondrial function, endoplasmic reticulum stress and the immune response. Furthermore, this review addresses potential treatment strategies and associated pitfalls as well as lifestyle interventions that could benefit people with an at risk APOE4 genotype.

Keywords: Apolipoprotein E isoform; Endoplasmic reticulum stress; Immune function; Mitochondrial function; Oxidative stress; Therapeutic intervention.

Fig. 1

Overview on the role of apolipoprotein E (APOE) in the three main pathways of plasma lipoprotein metabolism. In the exogenous pathway, chylomicrons (CM) are generated in the intestine from dietary fat and cholesterol and enter the systemic circulation, where they acquire APOE. CM are lipolyzed by lipoprotein lipase (LPL) and form CM remnants (CMR). Peripheral tissues, e.g., skeletal muscle and adipose tissue, take up released free fatty acids (FFA) and cholesterol. CMR undergo hepatic clearance after APOE-mediated binding to cell surface receptors, e.g., low density lipoprotein (LDL) receptor (LDLR) or LDLR-related protein (LRP) and heparan sulfate proteoglycan (HSPG) pathways. In the endogenous pathway, very low density lipoproteins (VLDL) are synthesized and secreted by the liver. LPL and hepatic lipase (HL) cause the release of FFA and the formation of VLDL remnants which can be cleared by the liver by APOE-mediated uptake (see above). Complete hydrolysis of VLDL results in the formation of LDL which lack APOE (LDL contain APOB-100 which mediates cellular uptake). The reverse cholesterol transport (RCT) enables excess cholesterol to be redirected from peripheral tissues to the liver via high density lipoproteins (HDL) that comprise APOE. APOE apolipoprotein E, CM chylomicron, CMR CM remnant, FFA free fatty acids, HDL high density lipoprotein, HL hepatic lipase, HSPG heparan sulfate proteoglycan, IDL intermediate density lipoprotein, LDL low density lipoprotein, LDLR LDL receptor, LPL lipoprotein lipase, LRP LDL receptor-related protein, RCT reverse cholesterol transport. Figure prepared according to [22, 23, 176]