abnormalities of ldl metabolism

Abnormalities of LDL metabolismPhysiology, pathophysiology and treatments

Under the supervision of Dr. Mezei Zsófia

Leticia Szadai, Philomène Toquet and Erwan Williamson

Introduction

WHO : Prevalence of raised blood cholesterol, age : 25+

• Abnormalities of LDL metabolism associated with severe cardiovascular diseases.

• Disorders of fat metabolism correlate with plasma LDL-C level.• 2,6 million deaths per year.• Causes : unhealthy lifestyle and/or gene.

Lipoproteins • Differentiated by their densities, diameters and molecular weight. • VLDL <IDL <LDL <HDL• Apolipoproteins : serving lipids to targeted cells.

- Structural element- Ligands - Enzyme activators

Endogenous pathway

Reverse cholesterol pathway

LDL receptor • Remove 70% of LDL• Ligand = ApoB100 ( MTP is necessary

for its production)• ARH = binding and endocytosis• PCSK9 = receptor’s degradation in

lysosome

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Pathophysiology Increased synthesis

Reduce uptake by cell

Harmful LDL

LDL

synthesis

clearance

atherogenesis

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Acquired Metabolic syndrom Diabetes Hypothyroidism Hypercorticism Nephrotic syndrome Infection Ethanol intake Types of drugs MenopauseIncrease

synthesis

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Congenital LDLR defect familial

hypercholesterolemia ApoB defect familial defective ApoB-

100 PCSK9 mutation ARH mutation

Reduce hepatic uptake

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hepatocyteARH

LDLPCSK9

LDLR

SERBP

LDLR

PCSK9

ApoB

+lysosome

Normal uptake

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hepatocyteARH

LDL

PCSK9

mutLDLR

SERBP

mutLDLR

PCSK9

ApoB

+lysosome

FH uptake

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Congenital LDLR defect familial

hypercholesterolemia ApoB defect familial defective ApoB-

100 PCSK9 mutation ARH mutation

Reduce hepatic uptake

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hepatocyteARH

LDL

PCSK9

LDLR

SERBP

LDLR

PCSK9

mutApoB

+lysosome

FDB uptake

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Congenital LDLR defect familial

hypercholesterolemia ApoB defect familial defective ApoB-

100 PCSK9 mutation ARH mutation

Reduce hepatic uptake

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hepatocyteARH

LDL

LDLR

SERBP

LDLR

mutPCSK9

ApoB

+lysosome

PCSK9 mutation uptake

mutPCSK9

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Congenital LDLR defect familial

hypercholesterolemia ApoB defect familial defective ApoB-

100 PCSK9 mutation ARH mutation

Reduce hepatic uptake

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ARH

LDLPCSK9

LDLR

SERBP

LDLR

PCSK9

ApoB

+lysosome

ARH mutation uptake

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Sitosterolemia

oxLDL

sdLDL

Harmful LDL

sitosterol

cholesterol

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Sitosterolemia

oxLDL

sdLDL

Harmful LDL

• Oxidative stress

• Inflammation

• LOX-1 scavenger receptor

• Foam cells

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Sitosterolemia

oxLDL

sdLDL

Harmful LDL

Equal concentration of cholesterol

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TherapyAgainst increased synthesis Statins (HMG-CoA reductase

inhibitors)

Lipid-lowering agents –such as Vitamin B3, fibrates, 2-Azetidiones, bile-acid sequestrates, omega-3.

Lifestyle modification- dietary changes, exercise, behavioral therapy.

(Apolipoprotein A1 mimetics) http://www.medscape.com/viewarticle/706510_2

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Therapy

Against reduced hepatic uptake

PCSK9 inhibitors

MTP inhibitors (lomitapide)

Antisense oligonucleotide (mipomersen)

Ahn CH et al.: New drugs for treating dyslipidemia: beyond statins,2015

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Therapy

Against harmful LDL Mechanisms

CETP-inhibitors

Shinkai H. et al.: Cholesteryl ester transfer-protein modulator and inhibitors and their potential for the treatment of cardiovascular diseases. (2012)

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Thank you for your attention