Lipoproteins-Blazyk

8/7/2019 Lipoproteins-Blazyk

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Lipoprotein

Metabolism

Jack Blazyk


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Most figures and tables are from

Harpers Illustrated Biochemistry27th Edition (2006) web version

byRobert K. Murray, Daryl K. Granner, and Victor W.

Rodwell

[Chapters 25 & 26]

Click here for link


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Lipids in the Blood

Fatty Acids

Bound to albumin

Cholesterol, Triglycerides and Phospholipids

Transported by lipoproteins

Cholesterol can be free oresterified

Triglycerides must be degraded

extracellularly to be absorbed by cells


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Lipids in the Blood

Phospholipids

Phosphatidylcholine = Lecithin


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Role of Cholesterol

Component of cell membranes

Precursor of bile acids

Precursor of steroid hormones


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Metabolism of Cholesterol

Dietary or de novo synthesis

Precursor is Acetyl-CoA

Regulated by HMG-CoA

reductase

Receptor-mediated import


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Anatomy of a Lipoprotein

Fig. 25-1


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Apolipoproteins

Structural determinants of

lipoproteins

Enzyme cofactors

Ligands for binding to lipoprotein

receptors


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Table 251. Composition of the Lipoproteins in Plasma of Humans.

Lipoprotein Source Diameter

(nm)

Density

(g/mL)

Protein

(%)

Lipid

(%)

Main Lipid

Components

Apolipoproteins

Chylomicrons Intestine 901000 < 0.95 12 9899 Triacylglycerol A-I, A-II, A-IV,1

B-48, C-I, C-II,C-III, E

Chylomicron

remnants

Chylomicrons 45150 < 1.006 68 9294 Triacylglycerol,

phospholipids,cholesterol

B-48, E

VLDL Liver (intestine) 3090 0.951.006 710 9093 Triacylglycerol B-100, C-I, C-II,

C-III

IDL VLDL 2535 1.0061.019 11 89 Triacylglycerol,

cholesterol

B-100, E

LDL VLDL 2025 1.0191.063 21 79 Cholesterol B-100

HDL Liver, intestine, VLDL,

chylomicrons

Phospholipids,

cholesterol

A-I, A-II, A-IV,

C-I, C-II, C-III,D,

2EHDL1 2025 1.0191.063 32 68

HDL2 1020 1.0631.125 33 67

HDL3 510 1.1251.210 57 43

Pre-HDL3

< 5 > 1.210 A-I

Albumin / free fatty

acids

Adipose tissue > 1.281 99 1 Free fatty acids

Abbreviations: HDL, high-density lipoproteins; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; VLDL, very low density

lipoproteins.

1Secreted with chylomicrons but transfers to HDL.

2Associated with HDL2 and HDL3 subfractions.

3Part of a minor fraction known as very high density lipoproteins (VHDL).


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The formation and secretion of (A) chylomicrons by an intestinal cell and (B) very low

density lipoproteins by a hepatic cell. (RER, rough endoplasmic reticulum; SER, smoothendoplasmic reticulum; G, Golgi apparatus; N, nucleus; C, chylomicrons; VLDL, very low densitylipoproteins; E, endothelium; SD, space of Disse, containing blood plasma.) Apolipoprotein B, synthesizedin the RER, is incorporated into lipoproteins in the SER, the main site of synthesis of triacylglycerol. Afteraddition of carbohydrate residues in G, they are released from the cell by reverse pinocytosis.Chylomicrons pass into the lymphatic system. VLDL are secreted into the space of Disse and then into thehepatic sinusoids through fenestrae in the endothelial lining.

Fig. 25-2


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Triglyceride-Degrading Enzymes

LPL (Lipoprotein Lipase)

LPL is extracellular on the walls of blood

capillaries, anchored to the endothelium.

Triacylglycerol (TG) is hydrolyzed to free fatty

acids plus glycerol. Some of the released free

fatty acids return to the circulation (bound to

albumin) but the bulk is transported into thetissue (mainly adipose, heart, and muscle

(80%), while about 20% goes indirectly to the

liver.


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Triglyceride-Degrading Enzymes

HL (Hepatic Lipase)

HL is bound to the sinusoidal surface of livercells, where it also hydrolyzes TG to free fatty

acids plus glycerol. This enzyme, unlike LPL,

does not react readily with chylomicrons or

VLDL but is concerned with TG hydrolysis in

chylomicron remnants and HDL metabolism.


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Fig. 25-3

Metabolic fate of chylomicrons. (A, apolipoprotein A; B-48, apolipoprotein B-48; , apolipoprotein C; E,apolipoprotein E; HDL, high-density lipoprotein; TG, triacylglycerol; C, cholesterol and cholesteryl ester; P,phospholipid; HL, hepatic lipase; LRP, LDL receptor-related protein.) Only the predominant lipids are shown.


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Fig. 25-4

Metabolic fate of very low density lipoproteins (VLDL) and production of low-density

lipoproteins (LDL). (A, apolipoprotein A; B-100, apolipoprotein B-100; apolipoprotein C; E,apolipoprotein E; HDL, high-density lipoprotein; TG, triacylglycerol; IDL, intermediate-densitylipoprotein; C, cholesterol and cholesteryl ester; P, phospholipid.) Only the predominant lipids are

shown. It is possible that some IDL is also metabolized via the LRP.


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Enzymes andTransfer Proteins

LCAT (Lecithin:Cholesterol Acyltransferase) Formation of cholesterol esters in lipoproteins

ACAT (Acyl-CoA:Cholesterol Acyltransferase)

Formation of cholesterol esters in cells

CETP (Cholesterol EsterTransferProtein)


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Fig. 25-5

Metabolism of high-density lipoprotein (HDL) in reverse cholesterol transport. (LCAT,lecithin:cholesterol acyltransferase; C, cholesterol; CE, cholesteryl ester; PL, phospholipid; A-I,apolipoprotein A-I; SR-B1, scavenger receptor B1; ABCA 1, ATP binding cassette transporter A1.) Pre-HDL,HDL2, HDL3 - see Table 251. Surplus surface constituents from the action of lipoprotein lipase onchylomicrons and VLDL are another source of pre -HDL. Hepatic lipase activity is increased by androgens

and decreased by estrogens, which may account for higher concentrations of plasma HDL2 in women.


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Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transportmay be mediated via the ABCA 1 transporter protein (with pre-HDL as the exogenous acceptor)or the SR-B1 (with HDL3 as the exogenous acceptor). (C, cholesterol; CE, cholesteryl ester; PL,phospholipid; ACAT, acyl-CoA:cholesterol acyltransferase; LCAT, lecithin:cholesterolacyltransferase; A-I, apolipoprotein A-I; LDL, low-density lipoprotein; VLDL, very low densitylipoprotein.) LDL and HDL are not shown to scale.

Fig. 26-5


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Transport of cholesterol between the tissues in

humans. (C, unesterified cholesterol; CE, cholesterylester; TG, triacylglycerol; VLDL, very low densitylipoprotein; IDL, intermediate-density lipoprotein; LDL,low-density lipoprotein; HDL, high-density lipoprotein;ACAT, acyl-CoA:cholesterol acyltransferase; LCAT,lecithin:cholesterol acyltransferase; A-I, apolipoprotein

A-I; CETP, cholesteryl ester transfer protein; LPL,lipoprotein lipase; HL, hepatic lipase; LRP, LDL receptor-related protein.)

Fig. 26-6


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Clinical Implications of

Lipoproteins


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Blood Lipid Levels


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Blood Lipid Levels


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Initial detailed analysis of plasma LDL in control subjects and CHD patients with hypertriglyceridemiaand low HDL have revealed the presence of two distinct major lipoprotein phenotypes based on LDLsubclasses. One subclass is characterized by a predominance of large buoyant LDL particles (patternA), and the second subclass is characterized by small, dense LDL particles (pattern B). Pattern B isoften associated with hypertriglyceridemia and low HDL, and is frequently referred to as theatherogenic lipoprotein profile.

Franceschini, Am. J. Cardiol. 2001; 88 (12A): 9N-13N


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LDL size correlates positively with plasma HDL levels and negatively with plasma triglyceride concentrations,and the combination of small, dense LDL, decreased HDL cholesterol and increased triglycerides has been calledthe atherogenic lipoprotein phenotype. This partly heritable trait is a feature of the metabolic syndrome, and isassociated with increased cardiovascular risk.

LDL size seems to be an important predictor of cardiovascular events and progression of coronary artery disease,and a predominance of small, dense LDL has been accepted as an emerging cardiovascular risk factor by theNational Cholesterol Education Program Adult Treatment Panel III.

However, other authors have suggested that LDL subclass measurement does not add independent information tothat conferred by the simple LDL concentration, along with the other standard risk factors.7 Thus it remainsdebatable whether to measure LDL particle size for cardiovascular risk assessment, and if so, in which categoriesof patients.

Rizzo & Berneis, Q. J. Med. 2006; 99:1-14.

LDL Does Size Matter?


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From Medical Biochemistry,

Baynes & Dominiczak,

Mosby, 1999.


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Genetic Disorders

Familial Hypercholesterolemia

Types

* Heterozygous FH (incidence 1:500-1,000)

* Homozygous FH (incidence 1:1,000,000)Causes

Both forms are caused by the same

problem: a mutation in either the LDL

receptor or the ApoB protein. There is one

known ApoB defect (R3500Q) and amultitude of LDL receptor defects, the

frequency of which is different for each

population.


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Statins

Atorvastatin (Lipitor - Pfizer)

Cerivastatin - (Baycol - Bayer)

Fluvastatin (Lescol - Novartis)

Lovastatin (Mevacor - Merck)

Pravastatin (Pravachol - BMS)

Rosuvastatin (Crestor - AstraZeneca)

Simvastatin (Zocor- Merck)


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Statins


Withdrawn in 2001

Fluvastatin (Lescol - Novartis)

Lovastatin (Mevacor - Merck)

Pravastatin (

Pravachol - BM

S)




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Statins


Fluvastatin (Lescol - Novartis)Lovastatin (Mevacor - Merck)

Pravastatin (Pravachol - BMS)




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Statins

Comparison of Effects on Cholesterol Levels

Effect On:Drug Daily Dose

TC LDL HDL TG

Crestor 5-40mgD

33-46%

D

45-63%

I

8-14%

D

10-35%

Lescol 20-80mgD

17-27%D

22-36%I

3-9%D

12-23%

Lipitor 10-80mgD

25-45%D

35-60%I

5-9%D

19-37%

Mevacor 10-80mg

D

16-34%

D

21-42%

I

2-9%

D

6-27%

Pravachol 10-80mgD

16-27%D

22-37%I

2-12%D

11-24%

Zocor 5-80mgD

19-36%D

26-47%I

8-16%D

12-33%

http://www.drugdigest.org/DD/Comparison/NewComparison/0,10621,37-15,00.html


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Statin patents are expiring

Simvastatin (Zocor) 2006

Lipitor 2010 All statins by 2012

What to do?

Convert to OTC (e.g., Mevacor) Combine with other drugs (e.g., Vytorin)

Big Pharma Woes


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Your Health

FDA Weighs Statin Drug Sales

by Joanne Silberner

Morning Edition, December 13, 2007

Statin drugs that lower cholesterol have become

popular. Merck, which manufactures the statin drug,

Mevacor, thinks its product is safe enough to be soldwithout a prescription. An advisory committee for the

Food and Drug Administration will meet to discuss

whether that is a good idea.


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ZocorZetiaVytorin


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Disappointing results were announced from thelong-awaited ENHANCE trial (completed in 2006)

of the best-selling cholesterol drug Vytorin, which

combines the unique cholesterol drug Zetia with the

traditional statin drug Zocor(simvastatin). Vytorinwas found to be no better than simvastatin alone

for reducing plaque buildup in the carotid arteries.

In fact, patients taking Vytorin actually had slightly

more plaque buildup during the trial than thosetaking simvastatin alone.


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1/15/08 Steven E. Nissen, MD, chairman of the

department of cardiovascular medicine at theCleveland Clinic and a past president of the

American College of Cardiology, called the results

"a stunning reversal for Zetia and Vytorin."

"Zetia works only by blocking the absorption of

cholesterol, but it has not been shown to produce

any health benefits," he says. "I have been

skeptical of these drugs from the beginningbecause I wasn't sure that Zetia's mechanism of

cholesterol lowering would produce the same

benefits that we see with statins."


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New Drugs BeyondStatins?


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Pfizer - Torcetrapib

CETP Inhibitor

Development began

around 1990

First administered inhumans in 1999


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Torcetrapib had been regarded as Pfizer's most important

developmental drug and was predicted to become a top

selling medicine in the cardiovascular market. Pfizer had

invested $800 million in its development, with the hopethat it would have become available before the 2011

patent expiry of its leading cardiovascular drug, Lipitor.

Pfizer was developing a combination tablet containing

torcetrapib, a cholesteryl ester transfer protein (CETP)

inhibitor and high-density lipoprotein (HDL) cholesterol

enhancer, with Lipitor(atorvastatin), for the potential

treatment of atherosclerosis and hypercholesterolemia.


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Since December, Pfizer eliminated 10,000 jobs (10% of its

work force) and faced a corporate shakeup with the ouster

of the head of R&D. Expectations for other CETPinhibitors under development are guarded, with intense

scrutiny by the FDA, which will likely require very large

Phase III trials in light of torcetrapibs problems.

In December 2006, Pfizer announced that data from the

ILLUMINATE trial showed that the combination of Lipitorplus torcetrapib was linked to a 60% increase in mortality

rate and cardiovascular events compared to Lipitor

alone. Pfizer subsequently discontinued the development

of the drug following recommendations from the DataSafety Monitoring Board which was supervising the study.

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Lipoproteins-Blazyk