HDL-Cholesterol

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HDL-Cholesterol

• By
• Ashraf Reda MD
• Professor of Cardiology
• Head of Cardiology Department
• Menofia University

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Structure of HDL
-----
Surface Monolayer of Phospholipids and Free
Cholesterol
apoA-I
apoA-II
Hydrophobic Core of Triglyceride and Cholesteryl
Esters
Rye KA et al. Atherosclerosis 1999145227-238.
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Structure of high-density lipoprotein (A)
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Reverse cholesterol transport
Peripheral Tissue
Blood Excess cholesterol
Liver
Bile
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Reverse cholesterol transport and HDL metabolism
Bile
FC
A-1
A-1
CE
CE
FC
ABC1
LCAT
FC
CE
SR-B1
Nascent HDL from liver or intestine
Mature HDL
Macrophage
CE cholesterol ester FC free cholesterol
A-1 apolipoproteinA-1 ABC1 ATP-binding
cassettte protein-1 LCAT Lecithincholesterol
acyl transeferase SR-B1scavenger receptor class
B1
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HDL metabolism Reverse cholesterol transport
and the role of CETP
Bile
FC
A-1
A-1
CE
CE
FC
ABC1
FC
LCAT
SR-B1
CE
Nascent HDL from liver or intestine
Mature HDL
Macrophage
CETP
LDL receptor
SR-A
B
Oxidation
CE
VLDL/LDL
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Genes involved in HDL metabolism

• HDL assosciated Apos.
• Apo-A1
• Apo-E
• Apo-IV
• Modifying plasma enzymes and transfer protein
• LCAT- CETP- PLTP
• LPL- HL- Endoth. lipase
• Cellular and cell surface protein
• ABC1
• SR-B1

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Primary (genetic) causes of low HDL

• Apo-A1
• Complete Deficiency
• Mutation (Milano Apo-A1)
• LCAT
• Complete deficiency
• Partial (fish eye disease)
• ABC-1
• Tangier disease (homo- or hetero- zygos)
• Familial hypo alpha lipoproteinemia
• Unknown genetic A/E
• Metabolic syndrome
• FCH with low HDL
• Hypoalphalipoproteinemia

HDL
A-1
CE
Mature HDL
A-1
FC
ABC-1
FC
Macrophage
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HDL

• Reverse cholesterol transport(Apo-A1ABC-A1)
• Inhibition of adhesion molecules
• Antioxident
• Vasotonic effect
• Prevent LDL oxidation and deposition

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Novel therapeutic modalities

• Milano type-apo A1 acutely increase HDL
• CETP inhibitors
• Over expression of LCAT

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ACTIVATE ACAT inhibitor fails to reduce the
progression of atherosclerotic coronary disease
Nov 15, 2005 Michael O'Riordan
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Secondary causes of increased HDL

• Extensive regular aerobics
• High fat diet
• Regular substantial alcohol intake
• Estrogen replacement therapy
• Drugs
• Phenytoin

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HDL-raising effect of exercise

the Health, Risk Factors, Exercise Training, and
Genetics (HERITAGE) Family Study
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Drugs

• Fibrates
• Niacin
• Statins
• CB1 receptor blockers

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(No Transcript)
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VA-HIT LRIAL
Gemfibrozil 1200mg
TG 31
No LDL change
HDL 6
Risk reduction
MICHD death Stroke
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Plt0.001
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Blocking the over-activated endocannbinoid
system CB1 blockade
Central CB1 Blockade
Perepheral CB1 blockade (Adipose tissue)
Food intake
Exess abdominal fat
Adeponectin Insulin Resistence Alter
the atherogenic lipid profile CRP
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HDL cholesterol and triglyceride parameters in
the rimonabant- and placebo-treated groups
Scheen A. American Diabetes Association 2005
Scientific Sessions June 10-14, 2005 San Diego,
CA.
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RIO-LIPIDS Changes from baseline for the end
points in the intention-to-treat population
last-observation-carried-forward analysis
Després JP et al. N Engl J Med 2005 353
2121-2134.
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CB1
Lipoprotein lipase activity
Adipose tissue
---
TNF-a
Adiponectin
Fat accumulation in adipose T
---
Adeponectin
----


----
FA oxidation
Glucose uptake
FFA clearance
Insulin sensetivity
Muscle
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PROactive subgroup analysis Outcomes in patients
with type 2 diabetes and previous MI
TG 11 HDL 18
Erdmann E. American Heart Association Scientific
Sessions 2005 Nov 13-16, 2005 Dallas, TX.
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Statins are still the first line and LDL less
than 70-100 mg/dl is the primary target
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ADA recommendation
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Conclusions
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HDL mechanisms of benefit

• Reverse cholesterol transport
• Protections against LDL oxidation
• Anti-inflamatory

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HDL raising strategies

• Exercise, LSM and better diabetes control
• PPAR agonists and metformin treatment
• Fibrates, Niacin and CB1-RB
• Statins
• CETP inhibitors, LCAT expression
• Gene manipulations Apo A, ABC1

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Thank you