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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 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.



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 of CETP

  • 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 of CETP

  • 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 of CETP

  • 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 of CETP

  • 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: of CETP

  • 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 of CETP

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


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Drugs of CETP

  • Fibrates

  • Niacin

  • Statins

  • CB1 receptor blockers


Va hit lrial l.jpg
VA-HIT LRIAL of CETP

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 of CETP

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 intention-to-treat population

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
PROactive intention-to-treat populationsubgroup 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 intention-to-treat population

LDL less than 70-100 mg/dl

is the primary target


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ADA recommendation: intention-to-treat population


Conclusions l.jpg

Conclusions intention-to-treat population


Hdl mechanisms of benefit l.jpg
HDL: mechanisms of benefit intention-to-treat population

  • Reverse cholesterol transport

  • Protections against LDL oxidation

  • Anti-inflamatory


Hdl raising strategies l.jpg
HDL raising strategies intention-to-treat population

  • 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 intention-to-treat population


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