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