Apoprotein E as a lipid transport and signaling protein in the blood, liver, and artery wall

Apoprotein E (apoE) is synthesized by a number of tissues including the liver, brain, adipose tissue, and artery wall. The majority of apoE is found in the plasma associated with specific lipoprotein subclasses and is derived primarily from the liver. However the fact that apoE expression is sustained in nonhepatic tissues suggests that the local production must have some unique functional attribute. ApoE is involved in many steps in lipid and lipoprotein homeostasis, for the triglyceride-rich lipoproteins and for HDL. ApoE is also important for lipid homeostasis in the brain, artery wall, and adipose tissue through its synthesis by glial cells, adipocytes, and macrophages. In addition, nonlipid related functions have also been attributed to apoE, including effects on immune response and inflammation, oxidation, and smooth muscle proliferation and migration. Some of these effects have been shown to be dependent upon different domains of the protein, different concentrations, and lipidation state. Thus, this multifunctional protein impacts normal and pathophysiology at multiple levels. Apoprotein E (apoE) is synthesized by a number of tissues including the liver, brain, adipose tissue, and artery wall. The majority of apoE is found in the plasma associated with specific lipoprotein subclasses and is derived primarily from the liver. However the fact that apoE expression is sustained in nonhepatic tissues suggests that the local production must have some unique functional attribute. ApoE is involved in many steps in lipid and lipoprotein homeostasis, for the triglyceride-rich lipoproteins and for HDL. ApoE is also important for lipid homeostasis in the brain, artery wall, and adipose tissue through its synthesis by glial cells, adipocytes, and macrophages. In addition, nonlipid related functions have also been attributed to apoE, including effects on immune response and inflammation, oxidation, and smooth muscle proliferation and migration. Some of these effects have been shown to be dependent upon different domains of the protein, different concentrations, and lipidation state. Thus, this multifunctional protein impacts normal and pathophysiology at multiple levels. Apolipoprotein E (apoE) has received a great deal of attention as a risk factor for both atherosclerosis and Alzheimer's disease. Human apoE, in contrast to other species, exists in one of three major isoforms, designated E2, E3, and E4. Each of these isoforms exhibit isoform-specific effects on atherosclerosis and Alzheimer's disease (1Mahley R.W. Weisgraber K.H. Huang. Y. Apolipoprotein E: structure determines function from atherosclerosis to Alzheimer's disease to AIDS.J. Lipid Res. 2009; : S183-S188Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar, 2Pendse A.A. Arbones-Mainar J.M. Johnson L.A. Altenburg M.K. Maeda. N. Apolipoprotein E knock-out and knock-in mice: atherosclerosis metabolic syndrome beyond.J. Lipid Res. 2009; : S178-S182Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). ApoE is a 34 kDa glycoprotein, initially noted as a component of plasma VLDL and HDL. It specifically associates with subsets of lipoproteins and this differs by isoform (3Dong L.M. Weisgraber K.H. Human apolipoprotein E4 domain interaction. Arginine 61 and glutamic acid 255 interact to direct the preference for very low density lipoproteins.J. Biol. Chem. 1996; 271: 19053-19057Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar). Although evolutionarily derived from a common soluble apoprotein progenitor gene, apoE has properties that distinguish it from related apoproteins. Its closest structural apoprotein is apoA-I, which is found on bulk HDL and on large triglyceride-rich lipoproteins such as chylomicrons. In the lipid-free state, both proteins form a four-helix bundle with a more random-ordered hydrophobic C terminus. The N-terminal domain of apoE (residues 1–191) contains the LDL receptor binding domain and a major heparan sulfate proteoglycan (HSPG) binding domain (both in the vicinity of residues 140–150). The C-terminal domain is believed to be responsible for the initial binding of the protein to lipid. ApoE is characterized by its wide tissue distribution (4Driscoll D.M. Getz G.S. Extrahepatic synthesis of apolipoprotein E.J. Lipid Res. 1984; 25: 1368-1379Abstract Full Text PDF PubMed Google Scholar) and function (Fig. 1). Some of the protein is degraded prior to secretion, and a portion remains associated with HSPG on the cell surface (5Mahley R.W. Ji Z.S. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E.J. Lipid Res. 1999; 40: 1-16Abstract Full Text Full Text PDF PubMed Google Scholar, 6Kockx M. Jessup W. Kritharides L. Regulation of endogenous apolipoprotein E secretion by macrophages.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1060-1067Crossref PubMed Scopus (63) Google Scholar). While the liver is the major source of plasma apoE, apoE produced by other cell types also contribute to plasma levels. Though plasma apoE may enter these tissues, the fact that expression is sustained in the tissues suggests that the local production must have some unique functional attribute. In this brief review, we outline the role of apoE in lipid transport and discuss other functions attributed to apoE that impact on atherosclerosis and energy homeostasis. ApoE is involved in many steps of lipoprotein homeostasis. In the plasma, apoE is associated with VLDL, chylomicron remnants, and a subset of HDL particles. It is a high affinity ligand for the LDL receptor and its family members such as the LDL receptor related protein (LRP1), VLDL receptor, and apoE2 receptor (LPR8). ApoE interacts with these receptors and HSPG promoting the endocytic clearance of plasma lipoproteins, especially VLDL and remnant lipoproteins (5Mahley R.W. Ji Z.S. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E.J. Lipid Res. 1999; 40: 1-16Abstract Full Text Full Text PDF PubMed Google Scholar, 7Raffai R.L. Hasty A.H. Wang Y. Mettler S.E. Sanan D.A. Linton M.F. Fazio S. Weisgraber K.H. Hepatocyte-derived apoE is more effective than non-hepatocyte-derived apoE in remnant lipoprotein clearance.J. Biol. Chem. 2003; 278: 11670-11675Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). The liver is the major site for the clearance of apoE-containing lipoproteins. In addition to its ligand function, apoE can also influence other aspects of lipoprotein metabolism in the plasma. ApoE at high levels restricts VLDL lipolysis, in part by displacing the lipoprotein lipase activator apoprotein CII from the particle (8Huang Y. Ji Z.S. Brecht W.J. Rall Jr., S.C. Taylor J.M. Mahley R.W. Overexpression of apolipoprotein E3 in transgenic rabbits causes combined hyperlipidemia by stimulating hepatic VLDL production and impairing VLDL lipolysis.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2952-2959Crossref PubMed Scopus (78) Google Scholar). ApoA-I, the premier activator of LCAT, is much less efficient on large HDL particles and apoB-containing lipoproteins where apoE functions as the LCAT activator (9Matsuura F. Wang N. Chen W. Jiang X.C. Tall A.R. HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway.J. Clin. Invest. 2006; 116: 1435-1442Crossref PubMed Scopus (258) Google Scholar, 10Zhao Y. Thorngate F.E. Weisgraber K.H. Williams D.L. Parks J.S. Apolipoprotein E is the major physiological activator of lecithin-cholesterol acyltransferase (LCAT) on apolipoprotein B lipoproteins.Biochemistry. 2005; 44: 1013-1025Crossref PubMed Scopus (38) Google Scholar). ApoE may also influence the activity of hepatic lipase and cholesteryl ester transfer protein (CETP) (11Greenow K. Pearce N.J. Ramji D.P. The key role of apolipoprotein E in atherosclerosis.J. Mol. Med. 2005; 83: 329-342Crossref PubMed Scopus (184) Google Scholar). ApoE is also implicated on the anabolic side of VLDL homeostasis. High expression levels of hepatic apoE result in a notable increase in VLDL triglyceride secretion (11Greenow K. Pearce N.J. Ramji D.P. The key role of apolipoprotein E in atherosclerosis.J. Mol. Med. 2005; 83: 329-342Crossref PubMed Scopus (184) Google Scholar, 12Mensenkamp A.R. Jong M.C. Goor H.van Luyn M.J.A.van Bloks V. Havinga R. Voshol P.J. Hofker M.H. Dijk K.W. van Havekes L.M. al et Apolipoprotein E participates in the regulation of very low density lipoprotein-triglyceride secretion by the liver.J. Biol. Chem. 1999; 274: 35711-35718Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). The C-terminal domain is required for the promotion of VLDL triglyceride secretion, particularly the hydrophobic amino acids between residues 260 and 270 (13Kypreos K.E. Dijk K.W. Van Havekes L.M. Zannis V.I. Generation of a recombinant apolipoprotein E variant with improved biological functions. Hydrophobic residues (Leu-261, Trp-264, Phe-265, Leu-268, Val-269) of apoE can account for the apoE-induced hypertriglyceridemia.J. Biol. Chem. 2005; 280: 6276-6284Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). The multiple roles of apoE in VLDL homeostasis are concentration dependent with low levels of apoE sufficient to promote receptor-mediated lipoprotein clearance and higher concentrations required to induce hypertriglyceridemia. Although hepatocytes and Kupffer cells produce apoE, little attention has been paid to the role of the Kupffer cells in lipoprotein homeostasis. In contrast, intestinal enterocytes do not synthesize apoE. The apoE found on circulating chylomicron remnants is acquired either from other circulating lipoproteins or from other tissues. ApoE, like apoA-I, interacts with ABCA1 to generate nascent HDL particles (14Vedhachalam C. Marayanaswami V. Neto N. Forte T.M. Phillips M.C. Bielicki S.Lund-Katz, and J.M. The C-terminal lipid-binding domain of apolipoprotein E is a highly efficient mediator of ABCA1-dependent cholesterol efflux that promotes the assembly of high density lipoproteins.Biochemistry. 2007; 46: 2583-2593Crossref PubMed Scopus (95) Google Scholar). The C-terminal hydrophobic domain of apoE (residues 222–299) is necessary for its stimulation of ABCA1-dependent cholesterol efflux, so that apoE isoforms interact particles may also the of VLDL by hepatocytes with apoE in and to the cell surface Apolipoprotein E for and Thromb. Vasc. Biol. 2006; PubMed Scopus Google Scholar). ApoE may between HDL and triglyceride-rich as a lipid a apoE on HDL at the of lipid While nascent is produced primarily by hepatocytes or the distribution of apoE lipoprotein is of the tissue source R.L. Hasty A.H. Wang Y. Mettler S.E. Sanan D.A. Linton M.F. Fazio S. Weisgraber K.H. Hepatocyte-derived apoE is more effective than non-hepatocyte-derived apoE in remnant lipoprotein clearance.J. Biol. Chem. 2003; 278: 11670-11675Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). ApoE is found on HDL including particles in which it is the apoprotein and particles that also In HDL particles apoE are than HDL particles. may be related to in the of the on with so that apoE is to of the HDL Phillips S.Lund-Katz, and M.C. of domain structure and lipid to the of Lipid Res. PubMed Scopus Google Scholar, R.W. Y. Weisgraber K.H. cholesterol in its apoE and cholesterol Clin. Invest. 2006; 116: PubMed Scopus Google Scholar). low levels of hepatic lipase or high cholesterol HDL in the plasma. The apoE is a of in nonhepatic tissues. is HDL is in the of apoE and this is by X.C. W. Y. of high density lipoprotein in receptor apolipoprotein E and is by cholesteryl ester transfer protein Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). the HDL with or is in apoE. ApoE a role in the It is produced in the glial cells, where it functions as a cholesterol transport protein between and especially and is of the to lipoproteins, endogenous synthesis of cholesterol and this transport protein is important (1Mahley R.W. Weisgraber K.H. Huang. Y. Apolipoprotein E: structure determines function from atherosclerosis to Alzheimer's disease to AIDS.J. Lipid Res. 2009; : S183-S188Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar). tissue is a of triglyceride and has important metabolic including homeostasis and ApoE is in adipose tissue, primarily in adipocytes, also in macrophages apoE expression triglyceride and 2006; PubMed Scopus Google Scholar). tissue, of its is a source of of this apoE expression triglyceride and 2006; PubMed Scopus Google Scholar, K. K. VLDL in Thromb. Vasc. Biol. 2003; PubMed Scopus Google Scholar) and in apoE K. K. VLDL in Thromb. Vasc. Biol. 2003; PubMed Scopus Google Scholar, Y. K. Y. 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Apolipoprotein E activity and effects on by and 1996; PubMed Scopus Google Scholar, The receptor binding domain of apolipoprotein E is responsible for its 2005; 44: PubMed Scopus Google Scholar, T.M. P.J. Bielicki of LCAT, and factor in Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, S. K. C. and of and of atherosclerosis by apolipoprotein E.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google of expression in and K. L. R. Phillips M.C. al et effects of HDL and apoE by dependent Clin. Invest. PubMed Scopus Google Scholar, K. S.Lund-Katz, Phillips M.C. properties of the in smooth muscle 2008; Full Text Full Text PDF PubMed Scopus Google for apoE of cell and 2005; PubMed Scopus Google Scholar, Thorngate F.E. S. L. Williams D.L. apolipoprotein E (apoE) plasma levels in Thromb. Vasc. Biol. PubMed Scopus (26) Google Scholar, K. L. R. Phillips M.C. al et effects of HDL and apoE by dependent Clin. Invest. PubMed Scopus Google for apoE of cell and 2005; PubMed Scopus Google and L. of apoE on inflammation, and disease Res. 2008; PubMed Scopus Google L. of apoE on inflammation, and disease Res. 2008; PubMed Scopus Google Scholar, C. Apolipoprotein E immune by on the 2003; PubMed Scopus Google Scholar, S. L. M. al et pathways of 2005; PubMed Scopus Google Scholar, K. M. and Apolipoprotein E the response in Res. 2005; PubMed Scopus Google Scholar, R. R. C. K. al et Apolipoprotein E in smooth muscle Thromb. Vasc. Biol. 2007; PubMed Scopus Google to S. L. M. al et pathways of 2005; PubMed Scopus Google of and apolipoprotein smooth muscle in a apoE, apolipoprotein smooth muscle muscle cell proliferation to and to ApoE can and is in in the artery for apoE of cell and 2005; PubMed Scopus Google Scholar) and artery Thorngate F.E. S. L. Williams D.L. apolipoprotein E (apoE) plasma levels in Thromb. Vasc. Biol. PubMed Scopus (26) Google Scholar). In derived factor promotes and ApoE both by different for apoE of cell and 2005; PubMed Scopus Google Scholar). proliferation is by apoE binding to cell surface in of expression and The of the expression of by the other apoE through to migration. The of apoE with the The of apoE on is by its it not exhibit apoE isoform concentrations of apoE higher concentrations are necessary to proliferation in apoE plasma levels are to artery Thorngate F.E. S. L. Williams D.L. apolipoprotein E (apoE) plasma levels in Thromb. Vasc. Biol. PubMed Scopus (26) Google this suggests that is the in The influence of apoE on proliferation is enhanced by the stimulation of the of and its by apoE and apoE-containing HDL of heparan sulfate proteoglycans and Med. : Scholar). may apoE stimulation of The stimulation of HSPG synthesis by apoE may also influence cholesterol efflux from macrophages M. Jessup W. Kritharides L. Regulation of endogenous apolipoprotein E secretion by macrophages.Arterioscler. Thromb. Vasc. Biol. 2008; 28: 1060-1067Crossref PubMed Scopus (63) Google Scholar). In addition to the apoE, particularly its N-terminal also effects on by stimulating to of the receptor and expression of the K. L. R. Phillips M.C. al et effects of HDL and apoE by dependent Clin. Invest. PubMed Scopus Google Scholar). apoE is more effective than the lipid associated receptor this it not to be the LDL receptor, or HSPG K. S.Lund-Katz, Phillips M.C. properties of the in smooth muscle 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). ApoE has effects on and that apoE and apoE-containing lipoproteins the proliferation of and cells a receptor that is from the lipoprotein receptors in L. of apoE on inflammation, and disease Res. 2008; PubMed Scopus Google Scholar). ApoE the of the factor Although not the activity of of involving and derived from by are more effective in the of and and with secretion in cells C. Apolipoprotein E immune by on the 2003; PubMed Scopus Google Scholar). In the of the of cells by the of lipid by apoE an important role in of the lipid to the cell S. L. M. al et pathways of 2005; PubMed Scopus Google Scholar). are more to and (11Greenow K. Pearce N.J. Ramji D.P. The key role of apolipoprotein E in atherosclerosis.J. Mol. Med. 2005; 83: 329-342Crossref PubMed Scopus (184) Google Scholar, L. of apoE on inflammation, and disease Res. 2008; PubMed Scopus Google Scholar). are by apoE. is as production of the and in in response to a receptor that not to the effects of the hyperlipidemia K. M. and Apolipoprotein E the response in Res. 2005; PubMed Scopus Google Scholar). The increase in and by expression of apoE. ApoE also of not by other ApoE has also been shown to in by and its with R. R. C. K. al et Apolipoprotein E in smooth muscle Thromb. Vasc. Biol. 2007; PubMed Scopus Google Scholar). stimulation of protein activity to this of apoE. In apoE has been shown to LDL M. Apolipoprotein E activity and effects on by and 1996; PubMed Scopus Google Scholar) and this to its domain The receptor binding domain of apolipoprotein E is responsible for its 2005; 44: PubMed Scopus Google Scholar). The high levels of in the plasma of T.M. P.J. Bielicki of LCAT, and factor in Lipid Res. Full Text Full Text PDF PubMed Scopus Google and the levels of in LDL receptor with hepatic of apoE S. K. C. and of and of atherosclerosis by apolipoprotein E.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) are with apoE an role in It is from this brief that apoE is a multifunctional protein that has an impact on pathophysiology at many in the have not the influence of apoE on cells, and the homeostasis in and have the of apoE isoforms on these functions. Some of the of apoE lipoprotein and lipid homeostasis. Some are properties of or apoE. ApoE has and some of its properties are from one by the for one or other It is also from in that some of the functions of apoE low or levels of the The of of these highly effects of apoE have to be in the effects of apoE account of its lipidation state, its concentration and its of must be The of atherosclerosis is The of of apoE in local tissues and as a lipid-free apoprotein one to the of other of atherosclerosis to of