Abstract
Apolipoprotein E (ApoE) is a protein playing a pivotal role in lipid homeostasis since it regulates cholesterol, triglyceride and phospholipid metabolism in the blood and the brain. APOE gene regulates the expression of this protein and has three different alleles: ε2, ε3 and ε4. Carrying an APOE4 allele is recognised as a genetic risk factor of late-onset Alzheimer’s disease (LOAD) and coronary heart disease (CHD). Consuming fatty fish, rich in long chain omega-3 fatty acids (LC omega-3), seems to be associated with risk reduction of developing LOAD and CHD but this link seems not to hold in APOE4 carriers, at least in LOAD. In CHD trials, APOE4 carriers supplemented with LC omega-3 were categorized as differential responders to the treatment with regards to CHD risk markers. This is potentially because fatty acid metabolism is disturbed in APOE4 carriers compared to the non-carriers. More specifically, homeostasis of LC omega-3 is disrupted in carriers of APOE4 allele and this is potentially because they β-oxidize more LC omega-3 than the non-carriers. Therefore, there is a potential shift in fatty acid selection for β-oxidation towards LC omega-3 which are usually highly preserved for incorporation into cell membranes.
Highlights
Apolipoprotein E (ApoE) is a 34 kDa protein with 299 amino acids and it was first identified as a component of triglycerides-rich lipoproteins
apolipoprotein E epsilon 4 (APOE4) carriers does not increase degradation through β-oxidation which is opposed to what we reported in the non-carriers [97], (2) docosahexaenoic acid (DHA) kinetics appear to be rebalanced in APOE4 carriers, at least for βoxidation, supporting that an appropriate dose and duration of LC omega-3 could benefit this population
We found that APOE4 carriers with low EPA- or DHA-status at fasting were potentially the ones having the most disrupted LC omega-3 metabolism after receiving a DHA supplement because EPA relative % at 5 h compared to 0 h (∆) was significantly reduced in APOE4 carriers from the low-EPA or -DHA group in the Sf > 400 fraction [98]
Summary
Apolipoprotein E (ApoE) is a 34 kDa protein with 299 amino acids and it was first identified as a component of triglycerides-rich lipoproteins. Homozygous carriers of APOE4 have a 15-fold increased risk of late-onset Alzheimer’s disease (LOAD) as compared to the non-carriers [10,11]. It is unclear how APOE4 modulates LOAD pathology but neuropathological changes associated with LOAD such as β-amyloid (Aβ) plaque deposition occur as early as 30 years of age in APOE4 carriers [12]. One study reported that after controlling for LDL and HDL cholesterol, CHD risk was not associated with APOE genotype [24] This suggests that increased CHD risk in APOE4 carriers seems to be attributed to disturbances in lipid homeostasis and most notably with regards to TG, cholesterol and LDL metabolism. This review will focus on the current evidence on disturbed fatty acid metabolism in APOE4 carriers and whether this can contribute to their higher risk of developing cognitive decline and cardiovascular-related complications
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