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The human apolipoprotein E (ApoE) gene is located on the long arm of chromosome 19 and is an important TC transport protein in plasma, which plays a role in regulating TC content. ApoE acts by mediating LDO and VLDL endocytosis by binding to apoB and apoE. The ApoE gene contains four exons and three introns. Zhong et al. found that the two nucleic acids (rs429358 and rs7412) differed, resulting in three alleles ε2, ε3, and ε4, respectively encoding E2, E3, and E4ApoE proteins, and then it constitutes six genotypes of human E2/2, E3/3, E4/4, E2/3, E2/4, and E3/4. These six genotypes can be distinguished by isoelectric focusing of plasma VLDL proteins. Different genotypes differ in the amino acids encoded by positions 112 and 158. ApoE3 is cysteine at position 112, arginine at position 158, arginine for ApoE2, and cysteine for ApoE4. Amino acid differences in subtypes affect the structure of apolipoprotein E and its role in disease.
There are many reasons for differences in blood lipid levels between individuals. The affinity of the ApoE isoform encoded by the ApoE allele and its lipoprotein receptor and its metabolic rate in vivo may be an important reason. This is also the occurrence and development of ApoE and atherosclerosis. An important foundation of the relationship. Up to 75% of plasma apolipoprotein E is synthesized by hepatocytes. Other tissues such as the brain, spleen, fat cells, and macrophages also synthesize a certain amount of ApoE.
ApoE maintains the structural integrity of lipoproteins and promotes lipoprotein solubilization in the blood. It is also involved in lipid metabolism in both liver and non-hepatic tissues, regardless of both exogenous and endogenous lipoprotein metabolism depending on ApoE. The chylomicrons synthesize and secrete and transport dietary fat through the small intestine to the ApoE obtained in the circulation of liver and adipose tissue. The very low density lipoproteins secreted by the liver include ApoE and endogenous synthetic triglycerides, phospholipids and transport secretory granules, cholesterol. And cholesterol esters to peripheral tissues. In addition, ApoE can bind not only to members of the LDL receptor family but also to heparan sulfate protein polymerase on the cell surface and extracellular matrix.
ApoE and Diseases
During the research, it was found that ApoE has appeared in a variety of biological processes, and the role of ApoE has been more than lipid metabolism. ApoE gene is inextricably linked to the development of atherosclerosis. Mastroianno et al. believe that the ApoE gene may be a risk factor for cardiovascular disease, especially for peripheral vascular revascularization in patients with the advanced atherosclerotic vascular disease. In order to effectively diagnose and detect coronary heart disease and increase the prevention and treatment of coronary heart disease in the early stage, it is particularly important to determine the molecular genetic characteristics of CHD high-risk or susceptible population and to conduct early screening.
ApoE2 is an essential subtype of type III hyperlipoproteinemia (HLP III), which together with environmental effects leads to damage to the normal lipid clearance pathway. HLP III is characterized by a reduction and accumulation of chylomicron metabolism, a residue of very low density lipoproteins. Homozygous ε2 causes an increased risk of type III hyperlipoproteinemia.
Giau et al. clarified the formation of ApoE and its role in lipid redistribution into neural central cells (CNS) and the neuropathological effects of neurotoxic ApoE fragments. ApoE is mainly produced by astrocytes, pericytes, microglia or certain pathological conditions (stressors, harmful substances, etc.). The results of ApoE cleavage are associated with cytoskeletal disruption and mitochondrial dysfunction. The ApoE isoform specifically binds to Aβ, resulting in Aβ-induced lysosomal leakage, followed by apoptosis in the cells.
Figure 1. APOE formation and its role in redistribution of lipids to the cells of CNS. (Giau,. et al. 2015)
ApoE4 is also associated with age-related diseases. Studies have found that ApoE4 is associated with Alzheimer's disease (AD), with approximately 60% to 80% of AD patients having at least one APOE4 allele. ApoE plays a vital role in lipid transport in the brain, helping to maintain and repair neurons, and the risk of death increases with age.
ApoE also regulates susceptibility and immunity in patients with infectious diseases. ApoE also increases the rate of HIV infection in vitro and promotes the death process in HIV patients. Studies have shown that the ApoE genotype is also associated with childhood obesity. Meta et al. have shown that obese children carrying the ε3 allele are protective factors, and carrying the ε4 allele may be associated with childhood obesity. Jacobs et al. found that the apolipoprotein E genotype is a potential risk factor for poor outcomes in women. Kulminski et al. also found that long-lived people over the age of 75 who carry the ε4 allele may prevent cancer.
ApoE and the Prognosis of Diseases
Carriers of the ApoE4 gene may have an increased demand for vitamin E in the diet. Compared with ApoE3, ApoE4 carriers have decreased vitamin E and increased degradation in the extrahepatic tissues. On the other hand, carriers of the ApoE4 gene have a higher absorption rate for calcium and vitamin D in food.
A study on anxiety and ApoE gene polymorphism in patients with coronary heart disease also showed that anxiety and ApoE gene polymorphism were associated with coronary heart disease patients. The ApoEε4 allele played an active role in the occurrence of anxiety in patients with coronary heart disease. Different individuals with ApoE gene polymorphism have different effects on lipid-lowering effects of drugs. Studies have shown that the TC of the ApoE ε4 gene carrier is lower than that of other alleles when taking statins to lower lipids.