Apolipoprotein E

1B68, 1BZ4, 1EA8, 1GS9, 1H7I, 1LE2, 1LE4, 1LPE, 1NFN, 1NFO, 1OEF, 1OEG, 1OR2, 1OR3, 2KC3, 2KNY, 2L7B34811816ENSG00000130203ENSMUSG00000002985P02649P08226NM_001302691NM_000041NM_001302688NM_001302689NM_001302690NM_009696NM_001305819NM_001305843NM_001305844NP_000032NP_001289617NP_001289618NP_001289619NP_001289620NP_001292748NP_001292772NP_001292773NP_033826Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body. It is implicated in Alzheimer's disease and cardiovascular disease.1b68: APOLIPOPROTEIN E4 (APOE4), 22K FRAGMENT1bz4: APOLIPOPROTEIN E3 (APO-E3), TRUNCATION MUTANT 1651ea8: APOLIPOPROTEIN E3 22KD FRAGMENT LYS146GLU MUTANT1gs9: APOLIPOPROTEIN E4, 22K DOMAIN1h7i: APOLIPOPROTEIN E3 22KD FRAGMENT LYS146GLN MUTANT1le2: STRUCTURAL BASIS FOR ALTERED FUNCTION IN THE COMMON MUTANTS OF HUMAN APOLIPOPROTEIN-E1le4: STRUCTURAL BASIS FOR ALTERED FUNCTION IN THE COMMON MUTANTS OF HUMAN APOLIPOPROTEIN-E1lpe: THREE-DIMENSIONAL STRUCTURE OF THE LDL RECEPTOR-BINDING DOMAIN OF HUMAN APOLIPOPROTEIN E1nfn: APOLIPOPROTEIN E3 (APOE3)1nfo: APOLIPOPROTEIN E2 (APOE2, D154A MUTATION)1or2: APOLIPOPROTEIN E3 (APOE3) TRUNCATION MUTANT 1651or3: APOLIPOPROTEIN E3 (APOE3), TRIGONAL TRUNCATION MUTANT 165 Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body. It is implicated in Alzheimer's disease and cardiovascular disease. APOE belongs to a family of fat-binding proteins called apolipoproteins. APOE interacts significantly with low-density lipoprotein receptor (LDLR), which is essential for the normal processing (catabolism) of triglyceride-rich lipoproteins. In peripheral tissues, APOE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism. In the central nervous system, APOE is mainly produced by astrocytes and transports cholesterol to neurons via APOE receptors, which are members of the low density lipoprotein receptor gene family. APOE is the principal cholesterol carrier in the brain. APOE qualifies as a checkpoint inhibitor of the classical complement pathway by complex formation with activated C1q The gene, APOE, is mapped to chromosome 19 in a cluster with apolipoprotein C1 (APOC-I) and the apolipoprotein C2. The APOE gene consists of four exons and three introns, totaling 3597 base pairs. APOE is transcriptionally activated by the liver X receptor (an important regulator of cholesterol, fatty acid, and glucose homeostasis) and peroxisome proliferator-activated receptor γ, nuclear receptors that form heterodimers with retinoid X receptors. In melanocytic cells APOE gene expression may be regulated by MITF. APOE is 299 amino acids long and contains multiple amphipathic α-helices. According to crystallography studies, a hinge region connects the N- and C-terminal regions of the protein. The N-terminal region (residues 1–167) forms an anti-parallel four-helix bundle such that the non-polar sides face inside the protein. Meanwhile, the C-terminal domain (residues 206–299) contains three α-helices which form a large exposed hydrophobic surface and interact with those in the N-terminal helix bundle domain through hydrogen bonds and salt-bridges. The C-terminal region also contains a low density lipoprotein receptor (LDLR)-binding site. APOE is polymorphic, with three major alleles (epsilon 2, epsilon 3, and epsilon 4): APOE-ε2 (cys112, cys158), APOE-ε3 (cys112, arg158), and APOE-ε4 (arg112, arg158). Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158, these differences alter APOE structure and function. Much remains to be learned about these APOE isoforms, including the interaction of other potentially protective genetic polymorphisms, so caution is advised before making determinant statements about the influence of APOE polymorphisms; this is particularly true as it relates to how APOE isoforms influence cognition and the development of Alzheimer's Disease. In addition, there is no evidence that APOE polymorphisms influence cognition in younger age groups (other than possible increased episodic memory ability and neural efficiency in younger APOE4 age groups), nor is there evidence that the APOE4 isoform places individuals at increased risk for any infectious disease. APOE transports lipids, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen. In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE. There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved LDLR family. APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. Defects in APOE result in familial dysbetalipoproteinemia aka type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron, VLDL and LDL. More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD), immunoregulation, and cognition. Though the exact mechanisms remain to be elucidated, isoform 4 of APOE, encoded by an APOE allele, has been associated with increased calcium ion levels and apoptosis following mechanical injury. In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing T cell proliferation, macrophage functioning regulation, lipid antigen presentation facilitation (by CD1) to natural killer T cell as well as modulation of inflammation and oxidation. APOE is produced by macrophages and APOE secretion has been shown to be restricted to classical monocytes in PBMC, and the secretion of APOE by monocytes is down regulated by inflammatory cytokines and upregulated by TGF-beta.