Reverse Cholesterol Transport

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A SEMINAR PRESENTATION ON

REVERSE CHOLESTEROL TRANSPORT


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OUTLINE

ACKNOWLEDGEMENT

INTRODUCTION

CHOLESTEROL OVERVIEW

CHOLESTEROL TRANSPORT

HDL BIOCHEMISTRY

REVERSE CHOLESTEROL TRANSPORT (RCT)

TRANSPORT PROTEINS IN RCTCLINICAL SIGNIFICANCE OF RCT

CONCLUSION

REFERENCES


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ACKNOWLEDGEMENT

Firstly, I acknowledge God Almighty for his

grace and enablement to commence andcomplete this report. I appreciate the effort and

selfless nature of my supervisor.

I appreciate the Head of Department, Faculty

and Staff of the Department of Biological

Sciences, Covenant University, who have also

contributed significantly to my knowledge in

Biochemistry. I also appreciate my Parents, for

their love and support.


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INTRODUCTION

About 40 years ago, John Glomset outlined thereverse cholesterol hypothesis. Glomsetproposed that HDL and LCAT might have anti-atherogenic functions related to their ability totransport cholesterol from peripheral tissue tothe liver for excretion (Tall, 2003).

In order to dispose of cholesterol, it istransported to the liver and intestine fromperiphery and is finally excreted via the feces.


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This pathway has been traditionally referred asreverse cholesterol transport or centripetal

cholesterol flux. Both free cholesterol and the esterified form are

involved in RCT.

Excess unesterified cholesterol is toxic to cells, andtherefore, cells have developed several ways toprotect themselves against cholesterol toxicity.

The return of this peripheral cholesterol to the

liver is necessary to balance cholesterol intake and denovo synthesis and thus to maintain whole bodysteady-state cholesterol metabolism (Cuchel and

Rader, 2006).


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What is cholesterol?

Cholesterol is a waxy, fat-like substance that isfound in all cells of the body.

Cholesterol is an amphiphatic lipid.

Cholesterol is derived from dietary source andde novosynthesis.


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PROPERTIES STRUCTUREcyclopentanoperhydrophenanthrene ring

Its molecular

formula is C27H46O. Its an organiccompound.

It has a meltingpoint of 148-150 0C

It has a boilingpoint of 360 0C

IUPAC name:(3)-cholest-5-en-3-ol.

Figure.1. Cholesterol Structure (Sterols:Cholesterol and cholesterol esters.

http://lipidlibrary.aocs.org/lipids/cholest/index.htm. Sourced on Sunday, 22 September 2013 at5p.m.).
http://lipidlibrary.aocs.org/lipids/cholest/index.htmhttp://lipidlibrary.aocs.org/lipids/cholest/index.htmhttp://lipidlibrary.aocs.org/lipids/cholest/index.htmhttp://lipidlibrary.aocs.org/lipids/cholest/index.htm


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FUNCTIONS

It plays a dual role as an essential structural component

of cellular membranes and a regulator of genetranscription, protein degradation, and enzyme activity(Liscum and Dahl, 1992).

It is required to build and maintain membrane.

It regulates membrane fluidity over the range ofphysiological temperature.

Within the cell membrane, cholesterol also functions in

intracellular transport, cell signaling and nerveconduction.

It is a precursor for the synthesis of vitamin D andsteroid hormones.


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SYNTHESIS

The major site of synthesis of cholesterol are Liver

Adrenal cortex

Testes Ovaries and

Intestine

occurs in the endoplasmic reticulum and thecytosol


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STEPS:

I. Synthesis of mevalonate occurs from acetyl-CoA.

II. Formation of Isoprenoid units frommevalonate and loss of CO

2

.

III. Condensation of isoprenoid units to formsqualene.

IV. Cyclisation of Squalene to the parent steroid

(lanosterol).

V. Cholesterol formation from lanosterol.


11/29Figure.2. Cholesterol biosynthetic pathway (Vance and Vance, 2002).


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CHOLESTEROL TRANSPORT

Blood is watery and cholesterol is fatty.

Just like oil and water, the two do not mix.

So, in order to travel in the bloodstream,cholesterol is carried in small packages calledlipoproteins.

The small packages are made of fat (lipid) on

the inside and proteins on the outside.

WHAT THEN ARE LIPOPROTEINS?


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Lipoproteins are complex aggregates of lipids andproteins that renders the lipids compatible with theaqueous environment of the body fluids and enabletheir transport throughout the body of allvertebrates to tissues where they are required.

Two kinds of lipoproteins carry cholesterolthroughout the body.

Low density lipoprotein (LDL) High density lipoprotein (HDL)


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LDL

LDL carries cholesterolfrom the liver to othertissues (extra-hepatictissues).

LDL is absorbed by targetcells through receptormediated endocytosis(RME).

A high LDL cholesterolleads to build up ofcholesterol in the arteries.

HDL

HDL carries cholesterolfrom other part of thebody back to the liver.

The liver then removes thecholesterol from the body.

HDL in the liver is nottaken up by RME, ratherthey dock in the surfacereceptor, deposit itscholesterol.

And depart as remnantwithout beingincorporated into the cellsinterior.


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BIOCHEMISTRY OF HDL

HDL carries about 33% of plasma cholesterol. Since it is associated with efflux and

redistribution of cholesterol in extra-hepatic

tissues, it is thought to play a prominent role inRCT.

HDL has a density of 1.063g/ml. It is made ofmostly proteins and small amount ofcholesterol.

The protein component (apoprotein) includes;


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Ap0 A-1

Ap0 A-2

Apo C

Apo D

Apo E

Apo A-1 is quantitatively and

functionally the most important(Berger, 1984).

It makes up 70% of HDL proteinand found in every HDL particle.

Freshly formed or secreted HDLexists briefly in the form ofbilayered discs containing a high

proportion of protein (mainlyapo A-I) and phospholipid

relative to cholesterol.


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Lipid poor Apo A-1 (bilayer disc form of HDL)interacts with ABCA1 on macrophage form cells,

forming nascent HDL particle.The nascent particle interacts with ABCG1 and

SR-B1 transporter to develop into a mature HDL

particle (Berger, 1984).At the present time the most convenient clinical

subdivision of HDL is into HDL2 and HDL3.

HDL2 is larger and less dense than HDL3enriched in cholesterol ester.

Matured HDL delivers cholesterol to the liverthrough : Direct and Indirect pathways.


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REVERSE CHOLESTEROL TRANSPORT

RCT is a pathway for plaque reduction (Cuchel

and Rader, 2006).From macrophages, cholesterol can be efflux

as free cholesterol either via ATP bindingcassette transporter A1 (ABCA1) with poor

lipidated Apo A-1 as acceptor or via ABCG1 withmore mature spherical HDL particles serving asreceptor (Linsel and Tall, 2005).

Additional efflux capacity might be provided byscavenger receptor class B type 1 (SR-B1) or byaqueous diffusion (Wang and Rader, 2007).


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Within HDL, cholesterol is esterified by lecithin-cholesterol acyl-transferase (LCAT).

This is done so to facilitate more uptake of freecholesterol.

Via the plasma compartment the effluxedcholesterol is transported in a reverse pathwayback to the liver.

HDL-derived cholesterol is then de-esterified

and secreted into the bile


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DIRECT PATHWAY

HDL interacts with SR-B1(scavenger receptor B1) onthe liver allowingcholesterol delivery.

The lipid-poor HDL particlecan be re-circulated torepeat the process of RCT.

INDIRECT PATHWAY

This is mediated by CETP(cholesteryl ester transfer

protein). CETP facilitates the

exchange of cholesterol inHDL for triglyceride in

triglyceride-rich apo Bparticle: VLDL and LDL.

HDL is enriched withtriglyceride and LDL with

cholesterol. LDL particle may go into

circulation or interact withLDL-receptors at the liver

cells and deposit thecholesteryl ester.


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Cholesterol lacks enzyme system which canbreak the steroid nucleus of cholesterol. So it is

not degraded.It is however converted to bile acid in the liver

and eliminated through the bile.


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Figure.3. A schematic diagram depicting the role of lipases in reverse

cholesterol transport (Rader, 2003).


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TRANSPORT PROTEINS INVOLVED IN RCT

ABCA1: Facilitates the efflux of unesterified

cholesterol and phospholipid. Genetic deficiency ofABCA1 causes Tangier disease.

LCAT: Necessary for the formation of maturedHDL and for remodeling of HDL lipoprotein particle(Dobiasova and Frohlich, 1999).

Traditionally, LCAT activity has been consideredanti-atherogenic. Its protective role depends on

i. concentration and quality of plasma HDL

ii. LDL particles

iii. availability of lipid transferring protein


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SR-B1: Mediates selective uptake of HDL

cholesterol by the liver .SR-B1 is expressed in macrophages and maycontribute to cholesterol efflux from

macrophages under certain conditions(Dobiasova and Frohlich, 1999).

CETP: mediates transfer of cholesteryl esterfrom HDL to apolipoprotein B-containinglipoproteins in exchange for triglyceride (Tall,2003).


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CLINICAL SIGNIFICANCE OF RCT

Early diagnosis of hypercholesterolemia (whichpromotes atheroma and leads to myocardial

infarction, stroke and peripheral vasculardisease).

Components of RCT useful in clinical trialincludes;

i. Enzyme activity

ii. Transport proteins

iii. Membrane modulators

iv. Apo-proteins

v. HDL classes.


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CONCLUSION

From the different steps that are important in

the RCT pathway, overall RCT might bedifferentially affected on different levels whichincludes;

i. The macrophage

ii. Transport of cholesterol through the plasmacompartment

iii. The uptake by the liver

iv. The excretion into the intestine, andv. The excretion from the body (Annema and

Tietge, 2012).


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REFERENCES

Annema, W. and Tietge, J.F. (2012). Regulation of reverse cholesterol

transport: A comprehensive appraisal of available animal studies. Nutrition &

Metabolism9: 1-18.

Berger, G.M.B. (1984). High-density lipoproteins, reverse cholesterol transportand atherosclerosis-recent developments. South African Medical Journal 65:503-506.

Colpo, A. (2005). LDL cholesterol: BAD cholesterol or BAD science?.American Journal of physicians and surgeons 10: 83-87.

Cuchel, M. and Rader, D.J. (2006). Macrophage reverse cholesterol transport:

Key to the regression of atherosclerosis? Circulation113

: 2548-2555.

Dobiasova, M. and Frohlich, J.J. (1999). Advances in understanding of the roleof lecithin cholesterol acyltransferase (LCAT) in cholesterol transport. ClinicaChimica Acta286: 257-258.

M P A d B h K M (2003) Ch l l S h i T


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Mayes, P.A. and Botham, K.M. (2003). Cholesterol Synthesis, Transport

and Excretion. In: Harpers illustrated biochemistry. (26). Lange Medical

Books/McGraw-Hill., pp: 219-220. ISBN-0-07-138901-6.

Linsel-Nitschke, P. and Tall, A.R. (2005). HDL as a target in the treatmentof atherosclerosis cardiovascular disease. Nature Reviews Drug Discovery

4: 193-205.

Liscum, L. and Dahl, N.K. (1992). Intracellular cholesterol transport.

Journal of lipid research33: 1239-1240.

Rader, D.J. (2003). Regulation of reverse cholesterol transport and clinical

implications.American Journal of Cardiology92: 42J-49J.

Tall, A.R. (2003). Role of ABCA1 in cellular cholesterol efflux and reverse

cholesterol transport. Arteriosclerosis Thrombosis Vascular Biology 23:

710-711.

Wang, X. and Rader, D.J. (2007). Molecular regulation of macrophagereverse cholesterol transport. Current Opinion in Cardiology22: 368-372.


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