Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease

Apolipoprotein E (apoE), a 34 kDa circulating glycoprotein of 299 amino acids, predominantly synthesised in the liver, associates with triglyceride-rich lipoproteins to mediate the clearance of their remnants after enzymatic lipolysis in the circulation. Its synthesis in macrophages initiates the formation of high density-like lipoproteins to effect reverse cholesterol transport to the liver. In the nervous system apoE forms similar lipoproteins which perform the function of distributing lipids amongst cells. ApoE accounts for much of the variation in plasma lipoproteins by three common variants (isoforms) that influence low-density lipoprotein concentration and the risk of atherosclerosis. ApoE2 generally is most favourable and apoE4 least favourable for cardiovascular and neurological health. The apoE variants relate to different amino acids at positions 112 and 158: cysteine in both for apoE2, arginine at both sites for apoE4, and respectively cysteine and arginine for apoE3 that is viewed as the wild type. Paradoxically, under metabolic stress, homozygosity for apoE2 may result in dysbetalipoproteinaemia in adults owing to impaired binding of remnant lipoproteins to the LDL receptor and related proteins as well as heparan sulphate proteoglycans. This highly atherogenic condition is also seen with other mutations in apoE, but with autosomal dominant inheritance. Mutations in apoE may also cause lipoprotein glomerulopathy. In the central nervous system apoE binds amyloid β-protein and tau protein and fragments may incur cellular damage. ApoE4 is a strong risk factor for the development of Alzheimer's disease. ApoE has several other physiological effects that may influence health and disease, including supply of docosahexaenoic acid for the brain and modulating immune and inflammatory responses. Genotyping of apoE may have application in disorders of lipoprotein metabolism as well as glomerulopathy and may be relevant to personalised medicine in understanding cardiovascular risk, and the outcome of nutritional and therapeutic interventions. Quantitation of apoE will probably not be clinically useful. ApoE is also of interest as it may generate peptides with biological function and could be employed in nanoparticles that may allow crossing of the blood-brain barrier. Therapeutic options may emerge from these newer insights.