1. Abnormalities of LDL metabolism
Physiology, pathophysiology and treatments
Under the supervision of Dr. Mezei Zsófia
Leticia Szadai, Philomène Toquet and Erwan Williamson

2. 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+

3. Lipoproteins
Differentiated by their densities, diameters and molecular weight.
VLDL <IDL <LDL <HDL
Apolipoproteins : serving lipids to targeted cells.
Structural element
Ligands
Enzyme activators

4. Endogenous pathway

5. Reverse cholesterol pathway

6. LDL receptor Remove 70% of LDL
Ligand = ApoB100 ( MTP is necessary for its production)
ARH = binding and endocytosis
PCSK9 = receptor’s degradation in lysosome

7. Pathophysiology Increased synthesis Reduce uptake by cell Harmful LDL
atherogenesis
LDL
The pathophysiology can occur in 3 different scenarios : INCREASE, DECREASE, HARMFUL.
clearance

8. Acquired Metabolic syndrom Diabetes Hypothyroidism Hypercorticism
Nephrotic syndrome
Infection
Ethanol intake
Types of drugs
Menopause
Mostly acquired, polyfactorial
Increase synthesis

9. Congenital LDLR defect  familial hypercholesterolemia
ApoB defect  familial defective ApoB- 100
PCSK9 mutation
ARH mutation
Reduce hepatic uptake
Mostly congenital, monogenic mutations

10. Normal uptake LDL ApoB PCSK9 LDLR hepatocyte ARH PCSK9 LDLR lysosome +
SERBP

11. FH uptake LDL ApoB PCSK9 mutLDLR hepatocyte ARH PCSK9 mutLDLR lysosome
Mutation of LDLR can lead to its dysregulation on many stage of its cycle : transcription, translation, traduction, uptake to cell membrane, binding to ApoB, recycling to the cell membrane
-> increase of LDL, ± lowering of LDLR
mutLDLR
lysosome +
SERBP

12. Congenital LDLR defect  familial hypercholesterolemia
ApoB defect  familial defective ApoB-100
PCSK9 mutation
ARH mutation
Reduce hepatic uptake

13. FDB uptake LDL mutApoB PCSK9 LDLR hepatocyte ARH PCSK9 LDLR lysosome +
Mutation of ApoB -> no binding between L/R
-> increase of LDL + normal LDLR activity
LDLR
lysosome +
SERBP

14. Congenital LDLR defect  familial hypercholesterolemia
ApoB defect  familial defective ApoB- 100
PCSK9 mutation
ARH mutation
Reduce hepatic uptake

15. PCSK9 mutation uptake LDL ApoB mutPCSK9 LDLR hepatocyte ARH mutPCSK9
Gain of function mutation of PCSK9 -> 2 dysregulations : lower binding L/R & more lysis of LDLR
-> increase LDL + decrease LDLR
LDLR
lysosome +
SERBP

16. Congenital LDLR defect  familial hypercholesterolemia
ApoB defect  familial defective ApoB- 100
PCSK9 mutation
ARH mutation
Reduce hepatic uptake

17. ARH mutation uptake LDL ApoB PCSK9 LDLR ARH PCSK9 LDLR lysosome +
Mutation of ARH -> no endocytosis of the complexe L/R
-> increase LDL + increase LDLR (and complexe L/R)
LDLR
lysosome +
SERBP

18. Sitosterolemia
oxLDL
sdLDL
sitosterol
Harmful LDL
cholesterol

19. Sitosterolemia oxLDL sdLDL Harmful LDL Oxidative stress Inflammation
LOX-1 scavenger receptor
Foam cells
Harmful LDL

20. Sitosterolemia oxLDL sdLDL Harmful LDL
Increase number of LDL -> less LDLR available + more infiltration in vessels walls
Harmful LDL
Equal concentration of cholesterol

21. Therapy Against 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)

22. 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

23. 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)

24. Thank you for your attention