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Apolipoprotein E

Definition:

APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids. APOE is a core component of plasma lipoproteins and is involved in their production, conversion and clearance. Apolipoproteins are amphipathic molecules that interact both with lipids of the lipoprotein particle core and the aqueous environment of the plasma. As such, APOE associates with chylomicrons, chylomicron remnants, very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL) but shows a preferential binding to high-density lipoproteins (HDL). It also binds a wide range of cellular receptors including the LDL receptor/LDLR, the LDL receptor-related proteins LRP1, LRP2 and LRP8 and the very low-density lipoprotein receptor/VLDLR that mediate the cellular uptake of the APOE-containing lipoprotein particles. Finally, APOE has also a heparin-binding activity and binds heparan-sulfate proteoglycans on the surface of cells, a property that supports the capture and the receptor-mediated uptake of APOE-containing lipoproteins by cells. A main function of APOE is to mediate lipoprotein clearance through the uptake of chylomicrons, VLDLs, and HDLs by hepatocytes. APOE is also involved in the biosynthesis by the liver of VLDLs as well as their uptake by peripheral tissues ensuring the delivery of triglycerides and energy storage in muscle, heart and adipose tissues. By participating in the lipoprotein-mediated distribution of lipids among tissues, APOE plays a critical role in plasma and tissues lipid homeostasis. APOE is also involved in two steps of reverse cholesterol transport, the HDLs-mediated transport of cholesterol from peripheral tissues to the liver, and thereby plays an important role in cholesterol homeostasis. First, it is functionally associated with ABCA1 in the biogenesis of HDLs in tissues. Second, it is enriched in circulating HDLs and mediates their uptake by hepatocytes. APOE also plays an important role in lipid transport in the central nervous system, regulating neuron survival and sprouting. APOE is also involved in innate and adaptive immune responses, controlling for instance the survival of myeloid-derived suppressor cells (By similarity). Binds to the immune cell receptor LILRB4. APOE may also play a role in transcription regulation through a receptor-dependent and cholesterol-independent mechanism, that activates MAP3K12 and a non-canonical MAPK signal transduction pathway that results in enhanced AP-1-mediated transcription of APP.; (Microbial infection) Through its interaction with HCV envelope glycoprotein E2, participates in the attachment of HCV to HSPGs and other receptors (LDLr, VLDLr, and SR-B1) on the cell surface and to the assembly, maturation and infectivity of HCV viral particles. This interaction is probably promoted via the up-regulation of cellular autophagy by the virus.

References:

[1]. Miklos Guttman, et al. Structure of the minimal interface between ApoE and LRP. J Mol Biol. 2010 Apr 30;398(2):306-19. [Content Brief]

[2]. Larbi Krimbou, et al. Molecular interactions between apoE and ABCA1: impact on apoE lipidation. J Lipid Res. 2004 May;45(5):839-48. [Content Brief]

[3]. Maaike Kockx, et al. Cell-specific production, secretion, and function of apolipoprotein E. J Mol Med (Berl). 2018 May;96(5):361-371. [Content Brief]

[4]. Ja Yeon Kim, et al. Regulation of Apolipoprotein E Trafficking by Hepatitis C Virus-Induced Autophagy. J Virol. 2018 Jun 29;92(14):e00211-18. [Content Brief]

[5]. Mi Deng, et al. LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. Nature. 2018 Oct;562(7728):605-609. [Content Brief]

[6]. Jon C Gonzales, et al. Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans. J Clin Invest. 2013 Jun;123(6):2742-51. [Content Brief]

[7]. C Wilson, et al. Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E. Science. 1991 Jun 28;252(5014):1817-22. [Content Brief]

[8]. Yu-Wen Alvin Huang, et al. ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion. Cell. 2017 Jan 26;168(3):427-441.e21. [Content Brief]

[9]. M Z Kounnas, et al. Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin. J Biol Chem. 1995 Jun 2;270(22):13070-5. [Content Brief]

[10]. L M Dong, et al. Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia. Nat Struct Biol. 1996 Aug;3(8):718-22. [Content Brief]

[11]. Yadong Huang, et al. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. Neurobiol Dis. 2014 Dec;72 Pt A:3-12. [Content Brief]

[12]. Y L Marcel, et al. Cholesteryl ester and apolipoprotein E transfer between human high density lipoproteins and chylomicrons. Biochim Biophys Acta. 1983 Feb 7;750(2):411-7. [Content Brief]

[13]. Philip B Verghese, et al. ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci U S A. 2013 May 7;110(19):E1807-16. [Content Brief]

[14]. Xiaoping Li, et al. Domains of apoE required for binding to apoE receptor 2 and to phospholipids: implications for the functions of apoE in the brain. Biochemistry. 2003 Sep 9;42(35):10406-17. [Content Brief]

[15]. Miklos Guttman, et al. Decoding of lipoprotein-receptor interactions: properties of ligand binding modules governing interactions with apolipoprotein E. Biochemistry. 2010 Feb 16;49(6):1207-16. [Content Brief]

[16]. R Arnon, et al. Effects of exogenous apo E-3 and of cholesterol-enriched meals on the cellular metabolism of human chylomicrons and their remnants. Biochim Biophys Acta. 1991 Oct 1;1085(3):336-42. [Content Brief]

[17]. L M Dong, et al. Site-directed mutagenesis of an apolipoprotein E mutant, apo E5(Glu3----Lys) and its binding to low density lipoprotein receptors. Biochem Biophys Res Commun. 1992 Sep 16;187(2):1180-6. [Content Brief]

[18]. Ji-Young Lee, et al. Apolipoprotein E likely contributes to a maturation step of infectious hepatitis C virus particles and interacts with viral envelope glycoproteins. J Virol. 2014 Nov;88(21):12422-37. [Content Brief]

[19]. R C Kowal, et al. Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived from apoprotein E-enriched lipoproteins. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5810-4. [Content Brief]

[20]. J W Burgess, et al. The HepG2 extracellular matrix contains separate heparinase- and lipid-releasable pools of ApoE. Implications for hepatic lipoprotein metabolism. J Biol Chem. 1998 Mar 6;273(10):5645-54. [Content Brief]

[21]. A M Fagan, et al. Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a ligand for the low density lipoprotein receptor-related protein. J Biol Chem. 1996 Nov 22;271(47):30121-5. [Content Brief]

[22]. W A Mann, et al. Dominant expression of type III hyperlipoproteinemia. Pathophysiological insights derived from the structural and kinetic characteristics of ApoE-1 (Lys146-->Glu). J Clin Invest. 1995 Aug;96(2):1100-7. [Content Brief]

[23]. Z S Ji, et al. Heparan sulfate proteoglycans participate in hepatic lipaseand apolipoprotein E-mediated binding and uptake of plasma lipoproteins, including high density lipoproteins. J Biol Chem. 1997 Dec 12;272(50):31285-92. [Content Brief]

[24]. E Sehayek, et al. Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low density lipoprotein receptor pathway. J Biol Chem. 1991 Sep 25;266(27):18259-67. [Content Brief]

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