Abnormalities of LDL metabolism Physiology, pathophysiology and treatments er the supervision of Dr. Mezei Zsófia cia Szadai, Philomène Toquet and Erwan Williamson
Jan 18, 2018
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