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HDL-Cholesterol. By Ashraf Reda MD Professor of Cardiology Head of Cardiology Department Menofia University. Structure of HDL. -----. Surface Monolayer of Phospholipids and Free Cholesterol. apoA-I. apoA-II. Hydrophobic Core of Triglyceride and Cholesteryl Esters.

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HDL-Cholesterol

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Hdl cholesterol l.jpg

HDL-Cholesterol

By

Ashraf Reda MD

Professor of Cardiology

Head of Cardiology Department

Menofia University


Structure of hdl l.jpg

Structureof HDL

-----

Surface Monolayer of Phospholipids and Free Cholesterol

apoA-I

apoA-II

Hydrophobic Core of Triglyceride and Cholesteryl Esters

Rye KA et al. Atherosclerosis 1999;145:227-238.


Slide3 l.jpg

Structure of high-density lipoprotein (A)


Slide4 l.jpg

Reverse cholesterol transport

Peripheral

Tissue

Blood

Excess cholesterol

Liver

Bile


Slide5 l.jpg

Reverse cholesterol transport and HDL metabolism

Bile

FC

A-1

A-1

CE

CE

FC

ABC1

LCAT

SR-B1

CE

FC

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= Lecithin:cholesterol acyl transeferase;

SR-B1=scavenger receptor class B1


Slide6 l.jpg

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


Genes involved in hdl metabolism l.jpg

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


Primary genetic causes of low hdl l.jpg

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


Slide9 l.jpg

HDL

  • Reverse cholesterol transport(Apo-A1—ABC-A1)

  • Inhibition of adhesion molecules

  • Antioxident

  • Vasotonic effect

  • Prevent LDL oxidation and deposition


Novel therapeutic modalities l.jpg

Novel therapeutic modalities

  • Milano type-apo A1 acutely increase HDL

  • CETP inhibitors

  • Over expression of LCAT


Secondary causes of increased hdl l.jpg

Secondary causes of increased HDL:

  • Extensive regular aerobics

  • High fat diet

  • Regular substantial alcohol intake

  • Estrogen replacement therapy

  • Drugs

  • Phenytoin


Hdl raising effect of exercise l.jpg

HDL-raising effect of exercise

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


Slide13 l.jpg

Drugs

  • Fibrates

  • Niacin

  • Statins

  • CB1 receptor blockers


Va hit lrial l.jpg

VA-HIT LRIAL

Gemfibrozil 1200mg

TG 31%

No LDL change

HDL 6%

Risk reduction

MI+CHD death

+Stroke

24%

P<0.001


Slide16 l.jpg

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


Hdl cholesterol and triglyceride parameters in the rimonabant and placebo treated groups l.jpg

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.


Rio lipids changes from baseline for the end points in the intention to treat population l.jpg

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.


Slide19 l.jpg

CB1

Lipoprotein lipase

activity

Adipose tissue

---

TNF-a

Adiponectin

Fat accumulation

in adipose T

---

Adeponectin

----

+

+

----

FA oxidation

Glucose uptake

FFA clearance

Insulin sensetivity

Muscle


Proactive subgroup analysis outcomes in patients with type 2 diabetes and previous mi l.jpg

PROactivesubgroup 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:


Conclusions l.jpg

Conclusions


Hdl mechanisms of benefit l.jpg

HDL: mechanisms of benefit

  • Reverse cholesterol transport

  • Protections against LDL oxidation

  • Anti-inflamatory


Hdl raising strategies l.jpg

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


Slide26 l.jpg

Thank you


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