Lipoproteins
Metabolism and
Clinical Implications
Jack Blazyk
Why do we need
lipoproteins?
How do we store our energy reserves?
Carbohydrates <1%
Lipids
85%
Proteins
15%
Lipids are not very
soluble in water
Ester
O
R-C-
Phospholipids
Phosphatidylcholine = Lecithin
Lipids in the Blood
• Fatty Acids
<5%
• Bound to albumin
• Cholesterol, Triglycerides and Phospholipids
~50%
~15-20%
~30%
• Transported by lipoproteins
• Cholesterol can be free or esterified
~⅓
~⅔
• Triglycerides must be degraded extracellularly
to be absorbed by cells
Anatomy of a Lipoprotein
Fig. 25-1
Fig. 18.14
Lippincott’s Illustrated Reviews
Biochemistry - 5th Ed. - 2011
R. Harvey & D. Ferrier
Apolipoproteins
(or Apoproteins)
• They are the unique structural
determinants of lipoproteins
• They serve as enzyme cofactors
• They are ligands for binding to
lipoprotein receptors
Table 25-1. Composition of the Lipoproteins in Plasma of Humans
Lipoprotein
Source
Apolipoproteins
Chylomicrons
Intestine
[A-I, A-II, A-IV],1 B-48, C-II, E
Chylomicron remnants
Chylomicrons
B-48, E
VLDL
Liver (intestine)
B-100, C-II, E
IDL
VLDL
B-100, E
LDL
VLDL
B-100
HDL
Liver, intestine, VLDL,
chylomicrons
A-I, A-II, A-IV, C-II, D,2 E
HDL1
HDL2
HDL3
Preβ-HDL3
Albumin / free fatty
acids
A-I
Adipose tissue
Abbreviations: HDL, high-density lipoproteins; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; VLDL, very low
density lipoproteins.
1
Secreted with chylomicrons but transfers to HDL.
2
Associated with HDL2 and HDL3 subfractions.
3
Part of a minor fraction known as very high density lipoproteins (VHDL).
Fig. 18.13
Fig. 18.19
Lippincott’s Illustrated Reviews
Biochemistry - 5th Ed. - 2011
R. Harvey & D. Ferrier
How are dietary fats
transported?
Fig. 18.16
Lippincott’s Illustrated Reviews
Biochemistry - 5th Ed. - 2011
R. Harvey & D. Ferrier
Triglyceride-Degrading Enzymes
• LPL (Lipoprotein Lipase)
• extracellular enzyme on the walls of blood
capillaries, anchored to the endothelium
• TG is hydrolyzed to free fatty acids plus
glycerol
• Some of the released FFA enters circulation
(bound to albumin) but most is transported
into nearby tissue - mainly adipose, heart,
and muscle (80%), while about 20% is
transported to the liver
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.
Triglyceride-Degrading Enzymes
• HL (Hepatic Lipase)
• HL is bound to the sinusoidal surface of liver
cells
• Hydrolyzes TG to free fatty acids plus
glycerol (just like LPL)
• Specific for chylomicron remnants and HDL
Why do liver cells make VLDL?
How is cholesterol delivered
to tissues?
Fig. 18.17
Lippincott’s Illustrated Reviews
Biochemistry - 5th Ed. - 2011
R. Harvey & D. Ferrier
Fig. 18.20
Lippincott’s Illustrated Reviews
Biochemistry - 5th Ed. - 2011
R. Harvey & D. Ferrier
ACAT
Intracellular
Fig. 18.21
Lippincott’s Illustrated Reviews
Biochemistry - 5th Ed. - 2011
R. Harvey & D. Ferrier
How does HDL transport
cholesterol from the periphery to
the liver?
Fig. 18.23
?
Lippincott’s Illustrated Reviews
Biochemistry - 5th Ed. - 2011
R. Harvey & D. Ferrier
Fig. 18.18
LCAT
In HDL
Phosphatidylcholine (PC)
Lecithin:cholesterol
Acyltransferase
(LCAT)
Lecithin
Lyso-phosphatidylcholine
(Lyso-PC)
Lyso-lecithin
Fig. 18.21
Lippincott’s Illustrated Reviews - Biochemistry - 5th Ed. - 2011 - R. Harvey & D. Ferrier
• LCAT
(Lecithin:Cholesterol Acyltransferase)
• Formation of cholesterol esters in HDL
• ACAT
(Acyl-CoA:Cholesterol Acyltransferase)
• Formation of cholesterol esters inside cells
Fig. 18.29
Lippincott’s Illustrated Reviews - Biochemistry - 5th Ed. - 2011 - R. Harvey & D. Ferrier
Clinical Implications of
Lipoproteins
Data from Framingham Heart Study
Activation of LDL Receptors
LDL
Receptors
Liver
Cholesterol
LDL
Slide Source:
Lipids Online Slide Library
www.lipidsonline.org
Familial Hypercholesterolemia
LDL
Receptors
Liver
Cholesterol
x
LDL
Slide Source:
Lipids Online Slide Library
www.lipidsonline.org
Pre-2013 Lipid Guidelines
What drug therapies are
available to improve
blood lipid profiles?
Statins
LDL
Receptors
Liver
Acetyl-CoA
Statin
HMG-CoA
Reductase
LDL
Cholesterol
Slide Source:
Lipids Online Slide Library
www.lipidsonline.org
Statins
Rosuvastatin (Crestor - AstraZeneca) 2016
Fluvastatin (Lescol - Novartis) Dec 2012
Atorvastatin (Lipitor - Pfizer)
Nov 2011
Pravastatin (Pravachol - BMS)
2006
Simvastatin (Zocor- Merck)
2006
Lovastatin (Mevacor - Merck)
2001
Comparison of Available Statins
Drug
HMG-CoA
Plasma Half
Reductase IC50 Life (hours)
Effect of 40 mg/d on:
LDL
HDL
TG
Crestor
[rosuvastatin]
11.8 nM
19
- 63%
+ 10%
- 28%
Lipitor
[atorvastatin]
15.2 nM
14
- 50%
+ 6%
- 29%
Zocor
[simvastatin]
18.1 nM
2
- 41%
+ 12%
- 18%
Pravachol
[pravastatin]
55.1 nM
2
- 34%
+ 12%
- 24%
Mevacor
[lovastatin]
NA
2
- 34%
+ 9%
- 16%
Lescol
[fluvastatin]
17.9 nM
1
- 24%
+ 8%
- 10%
Adapted from British Journal of Cardiology 2004;11(2) Christopher J. Packard “Evolution of the HMG CoA
Reductase Inhibitors (Statins) in Cardiovascular Medicine”
Wish List for the Ideal Statin
producing more than one effect;
especially : having multiple
phenotypic expressions
Adapted from British Journal of Cardiology 2004;11(2) Christopher J. Packard “Evolution of the HMG CoA
Reductase Inhibitors (Statins) in Cardiovascular Medicine”
Pleiotropic Effects of Statins
(Cholesterol-independent?)
• Improved endothelial function
• Enhanced plaque stability
• Decreased oxidative stress, inflammation, and
thrombogenic response
• Beneficial effects on immune system, CNS, and
bone
Effects mediated by inhibition of isoprenoids (lipid
attachments for intracellular signaling molecules like Rho,
Ras, and Rac)??
What are Statin Side Effects?
• Muscle pain and damage (rhabdomyolysis)
• Liver damage
• Digestive problems
[Click for more detail]
• Rash or flushing
• Increased blood sugar or type 2 diabetes
• Neurological side effects
Comparison of Available Statins
Drug
HMG-CoA
Plasma Half
Reductase IC50 Life (hours)
Effect of 40 mg/d on:
LDL
HDL
TG
Crestor
[rosuvastatin]
11.8 nM
19
- 63%
+ 10%
- 28%
Lipitor
[atorvastatin]
15.2 nM
14
- 50%
+ 6%
- 29%
Zocor
[simvastatin]
18.1 nM
2
- 41%
+ 12%
- 18%
Pravachol
[pravastatin]
55.1 nM
2
- 34%
+ 12%
- 24%
Mevacor
[lovastatin]
NA
2
- 34%
+ 9%
- 16%
Lescol
[fluvastatin]
17.9 nM
1
- 24%
+ 8%
- 10%
Adapted from British Journal of Cardiology 2004;11(2) Christopher J. Packard “Evolution of the HMG CoA
Reductase Inhibitors (Statins) in Cardiovascular Medicine”
Pharmaceutical Intervention
Beyond Statins?
Vytorin
Ezetimibe - Zetia (Schering-Plough)
Simvastatin - Zocor (Merck)
FDA approved Zetia in 2002
FDA approved Vytorin in 2004
Zocor patent expired in 2006
ENHANCE Trial Aftermath
• April 2006 - ENHANCE trial completed
• March 2008 - ENHANCE results released
• November 2009 - Merck acquires Schering-Plough
• February 2013 - Merck pays $688M settlement
Resurrection of Vytorin?
Correlation vs. Causation
Does lower LDL-cholesterol always result
in improved cardiac health?
Primary vs. Secondary Endpoints
Other drugs to improve lipid
profile and CV health?
Data from Framingham Heart Study
TG to
HDL
CE to
VLDL
LCAT
LCAT
(Niaspan ®)
TG to
HDL
LCAT
LCAT
CE to
VLDL
CETP Inhibitors
torcetrapib (Pfizer) M
dalcetrapib (Roche) M
anacetrapib (Merck) ?
evacetrapib (Lilly)
?
New 2013 AHA/ACC Guidelines
Statins for the Masses?
Obesity should be managed and treated like a disease
More Americans could benefit from statins
Cholesterol-lowering statin drugs could be prescribed to an estimated 33 million
Americans without cardiovascular disease who have a 7.5 percent or higher risk for
a heart attack or stroke within the next 10 years. This is a dramatic change from the
2002 federal cholesterol guideline, which recommended that people should only
take a statin if their 10-year risk level exceeded 20 percent. The old guideline only
considered a person’s risk for heart disease, leaving out the risk for stroke.
November 2013
November 2013
Click here
Case Vignette
Stephen, a 52-year-old white jogger with a BMI of 25,
wants you to assess his cardiovascular risks. He had
scheduled his visit after taking his father to another
physician to discuss his father’s blindness, which is
related to type 2 diabetes. Both his parents have
hypertension that is controlled with medication; neither
smokes.
Stephen is here to discuss the results of blood tests that
had been performed before the day of the visit.
Case Vignette
“I’m an accountant, Doc, and I live by the numbers. I
don’t want to be my father in 20 years,” he says. He tells
you that he has recently increased his running regimen
to 3 miles a day and that he smokes a half-pack a day
during tax season, when he is under stress.
“So what do the numbers say, and what’s this calculator
thing?” he asks. His total cholesterol level is 180 mg/dL,
HDL-cholesterol level is 35 mg/dL, triglyceride level is
150 mg/dL, and LDL-cholesterol level is 115 mg/dL. His
BP is 130/85 mm Hg.
Case Vignette
You think this is a great opportunity for shared decision
making and explain that although his LDL-cholesterol level
is not high, he has three risk factors for heart disease and
stroke (he has a low HDL-cholesterol level, smokes, and is
a man). You explain that the new AHA/ACC risk calculator
estimates his 10-year risk of an event such as a heart
attack or stroke at 10.9%, thereby requiring statin therapy.
The new guidelines assess the risks of death from
atherosclerotic heart disease, nonfatal heart attack, and
stroke and do not call for laboratory testing of LDLcholesterol once treatment with a statin is started.
Case Vignette
You also explain that the new guidelines have shifted the
approach to using statins and that they have generated
controversy. You tell him that, in fact, statin treatment
would not be recommended under the old guidelines,
which assess the risk of coronary heart disease, even
though the predicted risk would be higher. You have been
using the Adult Treatment Panel (ATP) III calculator in
your practice, and Stephen’s 10-year calculated risk
according to that guideline is 13%. At that level of risk,
with an LDL cholesterol level below 130 mg/dL, statin
therapy would not be advised.
Case Vignette
You tell him that you want more time to consider the new
guidelines, and the two of you agree to meet again in 2
weeks. Stephen, with his hand on the doorknob, says,
“Doc, I really want to know what you would do.”
After he leaves, your nurse tells you that your practice has
500 patients who may need similar reassessments if you
decide to use the new calculator.
Which one of the following three approaches would you
recommend for Stephen?
TREATMENT OPTIONS
1. Do not begin statin therapy.
2. Begin statin therapy, and monitor
LDL-cholesterol.
3. Begin statin therapy, but do not
monitor LDL-cholesterol.
It was supposed to be a moment of triumph. An august committee
had for the first time relied only on the most rigorous scientific
evidence to formulate guidelines to prevent heart attacks and
strokes, which kill one out of every three Americans. The group had
worked for five years, unpaid, to develop them. Then, at the annual
meeting of the American Heart Association, it all went horribly
awry.
Many leading cardiologists now say the credibility of the guidelines,
released Nov. 14, is shattered. And the troubled effort to devise
them has raised broader questions about what kind of evidence
should be used to direct medical practice, how changes should be
introduced and even which guidelines to believe.
“This was a catastrophic misunderstanding of how you go about
this sort of huge change in public policy,” said Dr. Steven Nissen, a
Cleveland Clinic cardiologist who is a past president of the
American College of Cardiology. “There will be a large backlash.”
[click here for full story]
On the Horizon
PCSK9
[Proprotein convertase subtilisin/kexin type 9]
PCSK9 is involved in regulation of LDL-receptor recycling
in hepatocytes
Monoclonal antibodies to PCSK9 inhibit its activity and promote
more LDL-receptor recycling, resulting in greater LDL uptake by
liver cells and lower LDL-cholesterol in the blood
For a short (4-min) video demonstrating the mechanism, click the link below:
http://www.cholesterolneversleeps.com/pcsk9
PCSK9
[Proprotein convertase subtilisin/kexin type 9]