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Lipoproteins

Md. Abdur Rakib, PhD Associate Professor

Dept. of Biochemistry and Molecular Biology

University of Rajshahi, Bangladesh

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Cholesterol and cholesteryl esters,

triacylglycerols and phospholipids, are

insoluble in water, but it must be moved from the tissue of origin to the tissues in which they will be stored or consumed.

To facilitate their transport, they are carried in the blood plasma as plasma lipoproteins,

macromolecular complexes of specific

carrier proteins, called apolipoproteins, and various combinations of phospholipids,

cholesterol, cholesteryl esters, and triacylglycerols.

Lipoproteins

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Lipoproteins are molecular complexes that consist of lipids and proteins (conjugated proteins). They function as transport vehicles for lipids in blood plasma. Lipoproteins deliver the lipid components (cholesterol, triacylglycerol etc.) to various tissues for utilization.

Lipoproteins

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Lipoproteins

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Approximate size and density of serum lipoproteins. Each family of lipoproteins exhibits a range of sizes and densities; this figure shows typical values. The width of the rings approximates the amount of each

component.

[Note: Although cholesterol and its esters are shown as one component in the center of each particle, physically cholesterol is a surface component whereas cholesteryl esters are located in the interior of the lipoproteins.]

Lipoproteins

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Four classes of lipoproteins, visualized in the electron microscope after negative staining. Clockwise from top left:

chylomicrons, 50 to 200 nm in diameter;

VLDL, 28 to 70 nm;

HDL, 8 to 11 nm; and LDL, 20 to 25 nm.

The particle sizes given are those measured for these samples; particle sizes vary considerably in different preparations.

For properties of lipoproteins, see Table 21–1.

Different combinations of lipids and proteins produce particles of different densities,

ranging from chylomicrons to high-density lipoproteins. These particles can be

separated by ultracentrifugation and visualized by electron microscopy.

Lipoproteins

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Lipoproteins Lipoproteins

Human plasma lipoproteins and

Properties

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Four major classes of lipoproteins are identified in human plasma, based on their separation by

electrophoresis.

Lipoproteins

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Apolipoproteins (“apo” designates the protein in its lipid-free form) combine with lipids to form several classes of

lipoprotein particles, spherical complexes with hydrophobic lipids in the core and hydrophilic amino acid side chains at the surface (Fig. 21–39a)

Apolipoproteins

Lipoproteins Lipoproteins

Each class of lipoprotein has a specific function, determined by its point of synthesis, lipid composition, and

apolipoprotein content.

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Metabolism of chylomicrons. CM = chylomicron; TAG = triacylglycerol; C = cholesterol; CE = cholesteryl esters. Apo B-48, apo C-II, and apo E are

apolipoproteins found as specific components of plasma lipoproteins.

The lipoproteins are not drawn to scale (see Figure 18.13 for details of the size and density of lipoproteins).

Metabolism of chylomicrons

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Metabolism of VLDL and LDL. TAG = triacylglycerol; VLDL = very-low- density lipoprotein; LDL = low-density-lipoprotein; IDL = intermediate- density lipoprotein; C = cholesterol; CE = cholesteryl esters. Apo B-100, apo C-II, and apo E are apolipoproteins found as specific components of plasma lipoproteins. Lipoproteins are not drawn to scale (see Figure 18.13 for details of the size and density of lipoproteins).

Metabolism of VLDL and LDL Metabolism of VLDL and LDL

Metabolism of VLDL

VLDLs are produced in the liver. They are composed predominantly of endogenous triacylglycerol (approximately 60%),and their function is to carry this lipid from the liver (site ofsynthesis) to the peripheral tissues. There, the triacylglycerol is degraded by lipoprotein lipase

1. Release of VLDL:

VLDL are secreted directly into the blood by the liver as nascent VLDL particles containing apo B- 100. They must obtain apo C-II and apo E from circulating HDL (see Figure 18.17). As with chylomicrons, apo C-II is required for activation of lipoprotein lipase.

2. Modification of circulating VLDL:

As VLDL pass through the circulation, triacylglycerol is degraded by lipoprotein lipase, causing the VLDL to decrease in size and become denser. Surface

components, including the C and E apoproteins, are returned to HDL, but the particles retain apo B-100.

Finally, some triacylglycerols are transferred from VLDL to HDL in an exchange reaction that

concomitantly transfers some cholesteryl esters from HDL to VLDL. This exchange is accomplished by cholesteryl ester transfer protein

3. Production of LDL from VLDL in the plasma:With these modifications, the VLDL is converted in the plasma to LDL. Intermediatesized particles, the intermediate-density lipo proteins (IDL) or VLDL remnants, are observed during this transition. IDLs can also be taken up by cells through receptor-mediated endocytosis that uses apo E as the ligand.

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Metabolism of VLDL and LDL. TAG = triacylglycerol; VLDL = very-low-density lipoprotein; LDL = low-density-lipoprotein; IDL = intermediate-density lipoprotein;

C = cholesterol; CE = cholesteryl esters. Apo B-100, apo C-II, and apo E are apolipoproteins found as specific components of plasma lipoproteins. Lipoproteins are not drawn to scale (see Figure 18.13 for details of the size and density of lipoproteins).

Metabolism of VLDL and LDL Metabolism of VLDL and LDL

LDL particles contain much less triacylglycerol than their VLDL predecessors, and have a high concentration of cholesterol and cholesteryl esters

1. Receptor-mediated

endocytosis:The primary function of LDL particles is to provide cholesterol to the peripheral tissues (or return it to the liver). They do so by binding to cell surface membrane LDL receptors that recognize apo B-100 (but not apo B-48).

Because these LDL receptors can also bind apo E, they are known as apo B- 100/apo E receptors. A summary of the uptake and degradation of LDL particles A similar mechanism of receptor-

mediated endocytosis is used for the cellular uptake and degradation of chylomicron remnants and IDLs by the liver.

2. Effect of endocytosed

cholesterol on cellular cholesterol homeo-stasis:The chylomicron

remnant-, IDL-, and LDL-derived

cholesterol affects cellular cholesterol content in several ways First, HMG CoA reductaseis inhibited by high cholesterol, as a result of which, denovocholesterol synthesis

decreases. Second, synthesis of new LDL receptor protein is reduced by decreasing the expression of the LDL receptor gene,

thus limiting further entry of LDL cholesterol into cells.

3. Uptake of chemically modified LDL by macrophage scavenger

receptors: In addition to the highly specific and regulated receptor -mediated pathway for LDL uptake described above, macrophages possess high levels of scavenger receptor activity. These receptors, known as scavenger receptor class A (SR-A), can bind a broad range of ligands, and mediate the endocytosis of chemically modified LDL in which the lipid components or apoB have been oxidized. Unlike the LDL receptor, the scavenger receptor is not down-regulated in response to increased intracellular cholesterol. Cholesteryl esters accumulate in macrophages

and cause their transformation into “foam” cells, which participate in the formation of atherosclerotic plaque

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Uptake of cholesterol by receptor-mediated endocytosis

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Role of foam cells in formation of atherosclerotic plaques

Role of foam cells in formation of atherosclerotic

plaques

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Metabolism of HDL. PC = phosphatidylcholine; lyso-PC =

lysophosphatidylcholine. LCAT= Lecithin cholesterol transferase. CETP

= cholesteryl ester transfer protein. ABCA1 = transport protein.

[Note: For convenience the size of VLDLs are shown smaller than HDL, whereas VLDLs are larger than HDL.]

Metabolism of HDL

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Metabolism of HDL Metabolism of HDL

HDL comprise a heterogeneous family of lipoproteins with a complex metabolism that is not yet completely understood.

HDL particles are formed in blood by the addition of lipid to apo A-1, an apolipo protein made by the liver and intestine and secreted into

blood. Apo A-1 accounts for about 70% of the apoproteins in HDL. HDL perform a number of important functions, including the following:

HDL is a reservoir of apolipoproteins:

HDL particles serve as a circulating reservoir of apo C-II (the apolipoprotein that is transferred to VLDL and chylomicrons, and is an activator of lipoprotein lipase), and apo E (the

apolipoprotein required for the receptormediated endocytosis of IDLs and chylomicron remnants).

HDL uptake of unesterified cholesterol:

Nascent HDL are diskshaped particles containing primarily phospholipid (largely phosphatidylcholine) and

apolipoproteins A, C, and E. They take up cholesterol from non-hepatic (peripheral) tissues and return it to the liver as

cholesteryl esters

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Esterification of cholesterol:

When cholesterol is taken up by HDL, it is immediately esterified by the plasma enzyme lecithin:cholesterol acyltransferase (LCAT, also known as PCAT, in which “P”

stands for phosphatidylcholine).

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Reverse cholesterol transport:

The selective transfer of cholesterol from peripheral cells to HDL, and from HDL to the liver for bile acid synthesis or

disposal via the bile, and to steroidogenic cells for hormone synthesis, is a key component of cholesterol homeostasis.

This is, in part, the basis for the inverse relationship seen between plasma HDL concentration and

atherosclerosis, and for HDL’s designation as the

“good” cholesterol carrier. Reverse cholesterol transport involves efflux of cholesterol from peripheral cells to HDL, esterification of cholesterol by LCAT, binding of thecholesteryl ester–rich HDL (HDL2) to liver and steroidogenic cells, the selective

transfer of the cholesteryl esters into these cells, and the release of lipid-depleted HDL (HDL3). The efflux of cholesterol from peripheral cells is mediated, at least in part, by the

transport protein, ABCA1.

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Reverse cholesterol transport. ApoA-I and HDLs pick up excess cholesterol from peripheral cells, with the participation of ABCA1 and ABCG1 transporters, and return it to the liver. In individuals with genetically defective ABCA1, the failure of reverse cholesterol transport leads to severe and early cardiovascular diseases: Tangier disease and familial HDL deficiency disease

Reverse cholesterol

transport.

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HDL (high-density lipoprotein), or “good”

cholesterol, absorbs cholesterol and carries it back to the liver. The liver then flushes it from the body. High levels of HDL cholesterol can lower your risk for heart disease and stroke.

LDL (low-density lipoprotein), sometimes called

“bad” cholesterol, makes up most of your body's cholesterol. High levels of LDL cholesterol raise your risk for heart disease and stroke.

LDL vs HDL

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Synthesis of cholesterol ester

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Cholesterol Synthesis and Transport Are Regulated at Several Levels

Oxysterols are 27-carbon derivatives of cholesterol, or by-products of

cholesterol biosynthesis, that contain additional oxygen functions as

hydroxyl, carbonyl, or epoxide groups (Schroepfer, 2000)

Regulation of cholesterol formation balances synthesis with dietary uptake and energy state.

Insulin promotes dephosphorylation (activation) of HMG-CoA reductase; glucagon promotes its phosphorylation (inactivation); and the AMP-dependent protein kinase AMPK, when activated by low [ATP] relative to [AMP], phosphorylates and inactivates it.

Oxysterol metabolites of cholesterol (for example, 24(S)-hydroxycholesterol) stimulate

proteolysis of HMG-CoA reductase.

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Regulation of cholesterol synthesis by sterol regulatory element-binding proteins (SREBPs)

Regulation of cholesterol synthesis by sterol regulatory

element-binding proteins (SREBPs)

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Liver X receptor (LXR) is a nuclear transcription factor activated by oxysterol ligands (reflecting high cholesterol levels), which integrates the metabolism of fatty acids, sterols, and glucose.

LXRα is expressed primarily in liver, adipose tissue, and macrophages; LXRα is present in all

tissues. When bound to an oxysterol ligand, LXRs form heterodimers with a second type of nuclear receptor, the retinoid X receptors (RXR), and the LXR-RXR dimer activates transcription from a set of genes (Fig. 21–45)including those for acetylCoA carboxylase (the first enzyme in fatty acid synthesis):

fatty acid synthase; the cytochrome P-450 enzyme CYP7A1, required for sterol conversion to bile acid;

apoproteins involved in cholesterol transport (apoC- I,

apoC-II, apoD, and apoE); the ABC transporters ABCA1 and ABCG1, involved in reverse cholesterol transport (see below); GLUT4, the insulin-stimulated glucose transporter of muscle and adipose tissue;

and SREBP1C. The transcriptional regulators LXR and SREBP therefore work together to achieve and maintain cholesterol homeostasis; SREBPs are activated by low levels of cellular cholesterol, and LXRs are activated by high cholesterol levels.

Finally, two other regulatory mechanisms influence cellular cholesterol level: (1) high intracellular concentrations of cholesterol activate ACAT, which increases esterification of cholesterol for storage, and (2) high cellular cholesterol levels diminish (via SREBP) transcription of the gene that encodes the LDL receptor,

reducing production of the receptor and thus the uptake of cholesterol from the blood

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