Transcript Lipid Digestion - Heritage College of Osteopathic Medicine

Lipoprotein
Metabolism
Jack Blazyk
Most figures and tables are from
Harper’s Illustrated Biochemistry
27th Edition (2006) web version
by
Robert K. Murray, Daryl K. Granner, and Victor W.
Rodwell
[Chapters 25 & 26]
Click here for link
Lipids in the Blood
• Fatty Acids
• Bound to albumin
• Cholesterol, Triglycerides and Phospholipids
• Transported by lipoproteins
• Cholesterol can be free or esterified
• Triglycerides must be degraded
extracellularly to be absorbed by cells
Lipids in the Blood
• Phospholipids
• Phosphatidylcholine = Lecithin
Role of Cholesterol
• Component of cell membranes
• Precursor of bile acids
• Precursor of steroid hormones
Metabolism of Cholesterol
• Dietary or de novo synthesis
• Precursor is Acetyl-CoA
• Regulated by HMG-CoA
reductase
• Receptor-mediated import
Anatomy of a Lipoprotein
Fig. 25-1
Apolipoproteins
• Structural determinants of
lipoproteins
• Enzyme cofactors
• Ligands for binding to lipoprotein
receptors
Table 25–1. Composition of the Lipoproteins in Plasma of Humans.
Lipoprotein
Source
Diameter
(nm)
Density
(g/mL)
Protein
(%)
Lipid
(%)
Main Lipid
Components
Apolipoproteins
Chylomicrons
Intestine
90–1000
< 0.95
1–2
98–99
Triacylglycerol
A-I, A-II, A-IV,
B-48, C-I, C-II,
C-III, E
Chylomicron
remnants
Chylomicrons
45–150
< 1.006
6–8
92–94
Triacylglycerol,
phospholipids,
cholesterol
B-48, E
VLDL
Liver (intestine)
30–90
0.95–1.006
7–10
90–93
Triacylglycerol
B-100, C-I, C-II,
C-III
IDL
VLDL
25–35
1.006–1.019
11
89
Triacylglycerol,
cholesterol
B-100, E
LDL
VLDL
20–25
1.019–1.063
21
79
Cholesterol
B-100
HDL
Liver, intestine, VLDL,
chylomicrons
Phospholipids,
cholesterol
A-I, A-II, A-IV,
C-I, C-II, C-III,
2
D, E
HDL1
20–25
1.019–1.063
32
68
HDL2
10–20
1.063–1.125
33
67
5–10
1.125–1.210
57
43
<5
> 1.210
HDL3
Preβ-HDL
3
Albumin / free fatty
acids
Adipose tissue
> 1.281
1
A-I
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
3Part
with HDL2 and HDL3 subfractions.
of a minor fraction known as very high density lipoproteins (VHDL).
Fig. 25-2
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, smooth
endoplasmic reticulum; G, Golgi apparatus; N, nucleus; C, chylomicrons; VLDL, very low density
lipoproteins; E, endothelium; SD, space of Disse, containing blood plasma.) Apolipoprotein B, synthesized
in the RER, is incorporated into lipoproteins in the SER, the main site of synthesis of triacylglycerol. After
addition 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 the
hepatic sinusoids through fenestrae in the endothelial lining.
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 the
tissue (mainly adipose, heart, and muscle
(80%), while about 20% goes indirectly to the
liver.
Triglyceride-Degrading Enzymes
• HL (Hepatic Lipase)
HL is bound to the sinusoidal surface of liver
cells, 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.
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.
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-density
lipoprotein; 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.
Enzymes and Transfer Proteins
• LCAT
(Lecithin:Cholesterol Acyltransferase)
• Formation of cholesterol esters in lipoproteins
• ACAT
(Acyl-CoA:Cholesterol Acyltransferase)
• Formation of cholesterol esters in cells
• CETP
(Cholesterol Ester Transfer Protein)
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.) Preβ-HDL,
HDL2, HDL3 - see Table 25–1. Surplus surface constituents from the action of lipoprotein lipase on
chylomicrons 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 HDL 2 in women.
Fig. 26-5
Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transport
may be mediated via the ABCA 1 transporter protein (with preβ-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:cholesterol
acyltransferase; A-I, apolipoprotein A-I; LDL, low-density lipoprotein; VLDL, very low density
lipoprotein.) LDL and HDL are not shown to scale.
Fig. 26-6
Transport of cholesterol between the tissues in
humans. (C, unesterified cholesterol; CE, cholesteryl
ester; TG, triacylglycerol; VLDL, very low density
lipoprotein; 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 receptorrelated protein.)
Clinical Implications of
Lipoproteins
Blood Lipid Levels
Blood Lipid Levels
Initial detailed analysis of plasma LDL in control subjects and CHD patients with hypertriglyceridemia
and low HDL have revealed the presence of two distinct major lipoprotein phenotypes based on LDL
subclasses. One subclass is characterized by a predominance of large buoyant LDL particles (pattern
A), and the second subclass is characterized by small, dense LDL particles (pattern B). Pattern B is
often associated with hypertriglyceridemia and low HDL, and is frequently referred to as the
atherogenic lipoprotein profile.
Franceschini, Am. J. Cardiol. 2001; 88 (12A): 9N-13N
LDL – Does Size Matter?
“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 called
the ‘atherogenic lipoprotein phenotype’. This partly heritable trait is a feature of the metabolic syndrome, and is
associated 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 the
National Cholesterol Education Program Adult Treatment Panel III.
However, other authors have suggested that LDL subclass measurement does not add independent information to
that conferred by the simple LDL concentration, along with the other standard risk factors.7 Thus it remains
debatable whether to measure LDL particle size for cardiovascular risk assessment, and if so, in which categories
of patients.”
Rizzo & Berneis, Q. J. Med. 2006; 99:1-14.
From Medical Biochemistry,
Baynes & Dominiczak,
Mosby, 1999.
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 a
multitude of LDL receptor defects, the
frequency of which is different for each
population.
From Medical Biochemistry,
Baynes & Dominiczak,
Mosby, 1999.
Statins
Atorvastatin (Lipitor - Pfizer)
Cerivastatin - (Baycol - Bayer)
Fluvastatin (Lescol - Novartis)
Lovastatin (Mevacor - Merck)
Pravastatin (Pravachol - BMS)
Rosuvastatin (Crestor - AstraZeneca)
Simvastatin (Zocor- Merck)
Statins
Atorvastatin (Lipitor - Pfizer)
Withdrawn in 2001
Fluvastatin (Lescol - Novartis)
Lovastatin (Mevacor - Merck)
Pravastatin (Pravachol - BMS)
Rosuvastatin (Crestor - AstraZeneca)
Simvastatin (Zocor- Merck)
Statins
Atorvastatin (Lipitor - Pfizer)
Fluvastatin (Lescol - Novartis)
Lovastatin (Mevacor - Merck)
Pravastatin (Pravachol - BMS)
Rosuvastatin (Crestor - AstraZeneca)
Simvastatin (Zocor- Merck)
Statins
Comparison of Effects on Cholesterol Levels
Drug
Effect On:
Daily Dose
TC
LDL
HDL
TG
Crestor
5-40mg
D
33-46%
D
45-63%
I
8-14%
D
10-35%
Lescol
20-80mg
D
17-27%
D
22-36%
I
3-9%
D
12-23%
Lipitor
10-80mg
D
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
10-80mg
D
16-27%
D
22-37%
I
2-12%
D
11-24%
Zocor
5-80mg
D
19-36%
D
26-47%
I
8-16%
D
12-33%
http://www.drugdigest.org/DD/Comparison/NewComparison/0,10621,37-15,00.html
Big Pharma Woes
• 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)
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 sold
without a prescription. An advisory committee for the
Food and Drug Administration will meet to discuss
whether that is a good idea.
Zetia
Vytorin
Zocor
Disappointing results were announced from the
long-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). Vytorin
was 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 those
taking simvastatin alone.
1/15/08 – Steven E. Nissen, MD, chairman of the
department of cardiovascular medicine at the
Cleveland 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 beginning
because I wasn't sure that Zetia's mechanism of
cholesterol lowering would produce the same
benefits that we see with statins."
New Drugs Beyond
Statins?
Pfizer - Torcetrapib
CETP Inhibitor
Development began
around 1990
First administered in
humans in 1999
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.
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 hope
that it would have become available before the 2011
patent expiry of its leading cardiovascular drug, Lipitor.
In December 2006, Pfizer announced that data from the
ILLUMINATE trial showed that the combination of Lipitor
plus 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 Data
Safety Monitoring Board which was supervising the study.
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 CETP
inhibitors under development are guarded, with intense
scrutiny by the FDA, which will likely require very large
Phase III trials in light of torcetrapib’s problems.