apolipoproteins role in atherogenesis · 2019. 11. 11. · cholesterol through the bile duct.22...

Int. J. Pharm. Sci. Rev. Res., 53(1), November - December 2018; Article No. 08, Pages: 34-37 ISSN 0976 – 044X

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Ali Jabbar Abdulhussein*, Shihab Hattab Mutlg Department of Pharmacology, College of Pharmacy, University of Baghdad, Iraq.

*Corresponding author’s E-mail: [email protected]

Received: 26-09-2018; Revised: 20-10-2018; Accepted: 03-11-2018.

ABSTRACT

Apolipoproteins play a significant role in lipid transport and metabolism through binding to lipid to form lipoproteins. Moreover, Apolipoproteins have several roles rather than lipid transportation such as co-factor for enzymes to transport the lipid molecules to cells and act as a ligand to lipoprotein cell receptors. Apolipoproteins are categorized into two main types and several subunits: exchangeable such as Apo B which anchored in lipoprotein and non-exchangeable like Apo A, E, D, and C which can transfer from one lipoprotein to another. Apo A1 and Apo B-100 are the major component of high-density lipoprotein (HDL) and low-density lipoprotein (LDL). These apolipoproteins are involved in many disorders and mainly dyslipidaemia, particularly atherosclerosis. Many studies are reported that Apo B is an atherogenic protein which can be oxidized and stimulate the immune cells to build up the plaque. However, Apo A, E and D may play as atheroprotective protein in different ways as shown by several experiment. In conclusion, Apolipoproteins have significant role in atherogenesis and its effect vary with different classes and subunits.

Keywords: Apolipoproteins, atherogenesis, lipoprotein.

INTRODUCTION

polipoproteins play a significant role in lipid transport and metabolism through binding to lipid to form lipoproteins.1,2 Apolipoproteins have

amphipathic property which have hydrophobic domain facing lipid and hydrophilic domain interfacing blood to facilitate lipids transport.1,2 Moreover, Apolipoproteins have other functions such as co-factor for enzymes to transport the lipid molecules to cells and act as a ligand to lipoprotein cell receptors.3 Apolipoproteins are classified into two main categories and several subunits: exchangeable such as Apo B which anchored in lipoprotein and non-exchangeable like Apo A, E, D, and C which can transfer from one lipoprotein to another.4,5 Apo A1 and Apo B-100 are the major component of HDL and LDL, respectively, which are involved in dyslipidaemia disorder, particularly atherosclerosis.

6,7,8

Atherosclerosis is accumulation of cholesterol in blood vessel walls which can lead to narrowing of arteries because of chronic inflammatory reaction. Therefore, this essay will review the role of apolipoprotein classes in developing and preventing of atherogenesis, in terms of atherogenic apolipoprotein (Apo B100) and atheroprotective proteins such as Apo A1, Apo E and Apo D as well as other classes like Apo C.

Apolipoprotein Apo B

Some apolipoproteins enhance atherogenesis process such as LDL is the most atherogenic factor because of the presence of Apo B protein, particularly (Apo B-100).9 Apo B100 has highly positive amino acids charge cluster which is called site B and this cluster plays a critical function in binding of LDL with negatively charge arterial proteins which are called proteoglycans.

9,10 Also, proteoglycans

are macromolecules consist of proteins and long chain carbohydrates and several proteoglycans presence in arteries such as chondroitin sulfate (CS) and dermatan sulfate (DS).9,10 Therefore, binding of Apo B100-lipoproteins with proteoglycans on endothelial vessels surface give rise to sequester of LDL on blood vessels. Enriched cholesterol macrophages enhance the production of extracellular proteoglycans which can increase the interaction and accumulation of LDL on arterial lumen and subsequently increase the cells up take of LDL particles.11,12,13

Hence, this sequestered LDL is exposed to oxidation, enzymatic degradation and aggregation by endothelial cells. Apo B100 is undergone an oxidative modification within the LDL which leads to release small peptides which induce inflammatory response so increase vascular permeability to oxidized LDL (ox-LDL), macrophages and monocytes.

14,15,16 They also reported that LDL diffuse to

the intima of blood vessels wall and further oxidation of LDL is occurred by free radicals to form more oxidized LDL particles.9,15 This ox-LDL is taken by macrophages which will be enriched with cholesterol to form layer of foam cells and fatty streaks. Macrophage foam cells present Apo B100 peptides to T cells as an antigen so Apo B100 neoantigen acts as chemoattractant to monocytes, macrophages and T cells which induce growing of atherogenic plaque via secretion of several of proinflammatory and cytokines mediators. Activation macrophages release more oxygen reactive radicals which can oxidize and modify more Apo B100 and increase the immunologic load. These immune cascades can lead to aggregation of platelets, proliferation of smooth muscle cells and secretion of proatherogenic cytokines such as IL-1, IL-18 and INF-gamma. As a consequence of inflammatory events, fibrous cap, necrotic lesion and

Apolipoproteins Role in Atherogenesis

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Review Article

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more foam cell formation induce degradation of the matrix and rapture of the endothelium which give raise to plaque atherosclerosis formation and narrowing of blood vessels.

9,15,16

Interestingly, as Apo B100 acts as antigen, consequently antibody is produced by B cells against this Apo B100 antigen. Although antibodies enhance more immune response and can lead to exacerbation of inflammation atherogenesis process in lesion site, there are many trials to produce a vaccine against atherosclerosis.17,18 Therefore, antibodies are found in cholesterol-fed mice and especially IgM can recognize Apo B100 motifs, specifically phosphorylcholine (PC) group, in ox-LDL, but not the native LDL, and these autoantibodies can block ox-LDL up taking by macrophages.9Also, identified the function of these anti Apo b100 antibodies in atherosclerosis by using phosphorylcholine (PC) group which is expressed in capsular epitopes in Streptococcus pneumonia.

9,19 They immunized LDLr -/- mice (mice with

high level of cholesterol 200-400 mg/dl and can increase with fat diet to 2000 mg/dl) with inactivated Streptococcal and they found high titre of IgM anti ox-LDL induction which reduced the atherosclerosis lesion through inhibit ox-LDL up taking by macrophages.9,19 The same findings were seen in human body of patients after recovered from pneumococcal infections and these observations suggested that IgM anti ox-LDL is exist in human body. Therefore, modulation of immune response via producing autoantibodies against Apo B100 epitopes can enhance atheroprotective effect. In short, all these inflammatory responses are induced by Apo B100 and the trials of modulation of Apo B100-induced immune reaction it may explain the crucial role of Apolipoprotein class B100 in developing of atherosclerosis.9

Apolipoprotein Apo A

However, other apolipoproteins work as atheroprotective. Apo A1 is a major protein of HDL and has an important function in lipid metabolism.

20,21 Apo A1

containing lipoprotein can transfer the cholesterol from peripheral tissues to liver which can excrete the cholesterol through the bile duct.

22 Also, Apo A1 act as

anti-oxidant, anti-inflammation and co enzyme for lecithin: cholesterol acyltransferase (LCAT) which transfer cholesterol to cholesterol ester in order to transport it by other lipoproteins such as VLDL and LDL to peripheral tissues as an energy source.

23,24

Importantly, Apo A1 is considered as cholesterol acceptor for free cholesterol from peripheral tissues and Apo A1 can esterify cholesterol to incorporate it into HDL core in order to remove the cholesterol through the bile.25 In atherosclerosis case, the macrophage foam cells, which are cholesterol loaded cells, secrete free cholesterol and Apo E in lesion site.25 So, Apo A1 is a cholesterol acceptor which can pick up and carry the cholesterol to liver via HDL. In addition, Apo E, will be discussed in more details below, which is secreted from Macrophage, can associate with phospholipid on HDL surface in order to increase

capacity of HDL loading with cholesterol and ultimately this cholesterol can be removed through liver. This means, Apo A1 containing HDL plays key role in regression of atherosclerosis.

25,26,27

Furthermore, Apo A1 containing lipoprotein (HDL) has antioxidant effect and can prevent LDL oxidation by transit interaction between HDL and LDL and this interaction will be discussed in more details below in Apo D part.

28 Apo A1 associates in antioxidant effect of HDL in

combination with LCAT and paraxonase-1 (PON1).28

Because of antioxidant effect of LCAT which can be inactivated by lipid peroxidase of lipoproteins and cell membrane, Apo A1 and PON1 prevent lipid peroxidase oxidation and deactivation of LACT and consequently keeping the antioxidant effect of LACT in HDL particles. It seems that inhibition of LDL oxidation by HDL is considered a significant atheroprotective effect of HDL lipoproteins.

28,29,30

Additionally, some studies suggested that Apo A1 prolong half-life of PGI2 prostacyclin, stabilizing factor, which promotes stabilization of platelets aggregation on vascular lesion which may slowdown atherogenesis. The alpha helix structure of Apo A1 allows to bind to PGI2 and prolong its time of activity as a result decrease of platelets accumulation, narrowing of arterial diameter and reduce the atherogenesis.31,32

Apolipoprotein Apo E

Other apolipoproteins involving in regression of atherogenesis is Apo E which is also considered as atheroprotective.33,34 Apolipoprotein E can be produced by liver but also macrophage rich cholesterol cells secret it in lesion site.35,36 Interestingly, Apo E has three main mechanisms and several minor effects to decrease developing of atherosclerosis.35 The first mechanism which is involved in lipid metabolism pathway and it is mentioned above about the role of Apo E in reverse cholesterol transport from peripheral tissues to live in the presence of Apo A1 containing lipoproteins (HDL).

35 Apo E

can also increase the loading capacity of HDL to carry more cholesterol to liver. 25,35 Secondly, Apo E can modify T cells activation and smooth muscle cells proliferation. Apo E regulates the inflammation response which is activated during atherogenesis and particularly intimal T lymphocytes activation and smooth muscle cells (SMCs) proliferation. Apo E can inhibit mitogen- activation proliferation of CD4 and CD8 T cells which can lead to suppress T lymphocytes activation. Inhibition of T cells activation give rise to inhibit of interleukin production and interferon (INF-gamma) which can accelerate the atherosclerosis formation. SMCs proliferation and migration are inhibited by Apo E through suppress oxidation of LDL and inhibit of inflammatory agonist platelet-derived growth factor.35,37

The third mechanism of Apo E is antioxidant effect, Apo E containing LDL shows reduction in LDL level of 8-iso-PGF2_-VI, which is an indicator of oxidative stress




36

mediated by lipid peroxidase.38,39 These findings enhance the idea of Apo E antioxidant effect toward LDL particles as a result Apo E inhibit macrophages mediate LDL oxidation and prevent formation of foam cells. These last two main mechanisms are considered as non-lipid metabolism pathways.

38 Other atheroprotective effects,

Apo E has a key role in HDL maturation by acting as a co enzyme for lecithin-cholesterol acyltransferase, LCAT, Hepatic Lipase HL and CETP cholesteryl ester transfer protein. Furthermore, Apo E increases the HDL-C clearance by liver through scavenger receptor B1.37,40

Additionally, Apo E increase hepatic clearance of lipoproteins through act as a ligand for LDL-receptor-related protein (LRP) and LDL receptor (LDLR).38 It can be seen that Apo E play a substantial role protective effects against atherosclerosis and this explain the idea of using Apo E knockout mice as atherosclerotic model in experiment.

Apolipoprotein Apo D

Apo D can have a function in regression of atheroma formation which is similar to Apo E, Apo D is associated with LCAT enzyme in HDL lipoprotein and play role in transferring of cholesterol ester and triglyceride between lipoproteins and particularly from VLDL to HDL.37,40 Surprisingly, Apo D promotes transient interaction between HDL and LDL, and HDL and cells.41 Importantly, these findings may explain the antioxidant effect of HDL containing Apo A1 against LDL as it was mentioned above in Apo A1 part. So, Apo D may have an influential role in preventing atherogenesis through mainly transport the cholesterol to HDL particles which carries the cholesterol to liver and secret it through bile. Apo D enhances antioxidant effects of Apo A1 containing lipoprotein HDL by binding HDL and LDL particles and prevent formation of ox-LDL which is considered the key step of atherosclerosis initiation in blood vessel walls.41,42

Apolipoprotein Apo C

Finally, other apolipoproteins such as Apo C which is a low molecular weight protein and has different functions according to its subclass such as CI, CII and CIII. For example, Apo CII is one of protein component of HDL, VLDL and chylomicron and this subclass can activate lipoprotein lipase enzyme which hydrolyse the triglyceride component to use it by different tissues as an energy source.

43 Deficiency of this Apo CII protein may

lead to hypertriglyceridemia. In contrast, Apo CIII acts as inhibition of lipoproteins lipase and prevent liver uptake of triglyceride. Apo C might involve in atherogenesis through indirect pathway and depends on its subunits.43

CONCLUSION

Apolipoproteins have significant role in atherogenesis and its effect vary with different classes and subunits. Some apolipoproteins such as Apo B100 act as thermogenic factors through enhance LDL biding to arterial proteoglycans and stimulate inflammatory reaction. Therefore, many studies have been conducted to

modulate the inflammatory response by creating vaccine against Apo B100 induced atherosclerosis. However, Apo A1 is an atheroprotective protein by reversing transportation of cholesterol from peripheral tissues to liver and excrete it through bile duct and also acts as co enzyme of LCAT. Furthermore, Apo A1 associate in antioxidant and stabilizer of PGI2 prostacyclin effects of HDL. In addition, Apo E has anti-atherogenesis effects via reversal transport of cholesterol from macrophage foam cells site and increase HDL loading capacity to carry cholesterol to liver. Also, Apo E involves in non-lipid metabolism protection mechanisms such as modifying the activity of T cells and inhibit smooth muscle cells proliferation, antioxidant, enhance HDL maturation and increase HDL-C clearance by liver. Apo D associates with LCAT activation and enhance antioxidant activity in HDL through transit interaction with LDL particles. While Apo C includes different functions according to its subunits, for example, Apo CII promotes liver up taking of triglycerides while Apo CIII inhibit this action and cause hypertriglyceridemia.

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Source of Support: Nil, Conflict of Interest: None.

apolipoproteins role in atherogenesis · 2019. 11. 11. · cholesterol through the bile duct.22...

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