Comprehensive description of various primary dyslipidemias, cholesterol transport and molecular mechanisms involved. View in slideshow after downloading for better experience. Prepared in Dec 2013.

1. Primary
Disorders of
Lipoprotein
Metabolism
Ashikh Seethy
Junior Resident
Maulana Azad Medical College
New Delhi-2

2. Overview
• Lipoproteins
• Transport of lipids
• Diseases due to abnormality of lipoproteins
• Molecular mechanisms
• Sites of action of drugs

3. Lipoprotein Electrophoresis Major
Chylomicrons Origin ApoB-48
Chylomicron remnants Slow pre-β ApoB-48
VLDL Pre-β ApoB-100
IDL Slow pre-β ApoB-100
LDL β ApoB-100
HDL α ApoA-I
Lp(a) Pre-β ApoB-100

4. Why is it that we have lipoproteins?

5. Apolipoprotein Primary Source Lipoprotein Association Function
ApoA-I Intestine, liver HDL, chylomicrons Structural protein for HDL Activates LCAT
ApoA-II Liver HDL, chylomicrons Structural protein for HDL
ApoA-IV Intestine HDL, chylomicrons Unknown
ApoA-V Liver VLDL, chylomicrons Promotes LPL-mediated triglyceride
lipolysis
Apo(a) Liver Lp(a) Unknown
ApoB-48 Intestine Chylomicrons Structural protein for chylomicrons
ApoB-100 Liver VLDL, IDL, LDL, Lp(a) Structural protein for VLDL, LDL, IDL,
Lp(a). Ligand for binding to LDL receptor
ApoC-I Liver Chylomicrons, VLDL, HDL Unknown
ApoC-II Liver Chylomicrons, VLDL, HDL Cofactor for LPL
ApoC-III Liver Chylomicrons, VLDL, HDL Inhibits lipoprotein binding to receptors
ApoE Liver Chylomicron remnants, IDL, HDL Ligand for binding to LDL receptor
ApoH Liver Chylomicrons, VLDL, LDL, HDL Platelet activation
ApoJ Liver HDL Unknown
ApoL Unknown HDL Unknown
ApoM Liver HDL Unknown

6. Transport of dietary lipids

7. Transport of endogenous lipids

8. Apo B-100 in VLDL and Apo B-48 in
Chylomicron. How?
Cytidine deaminase
How?

9. Disorders of lipoprotein metabolism

11. Phenotype I IIa IIb III IV V
Lipoprotein,
elevated
Chylomicrons LDL LDL and VLDL Chylomicron and
VLDL remnants
VLDL Chylomicrons
and VLDL
Triglycerides +++ N + ++ ++ +++
Cholesterol
(total)
+ +++ ++ ++ N/+ ++
LDL-cholesterol - +++ ++ - - -
HDL-cholesterol - - - N/- - N - - - - -
Plasma
appearance
Lactescent Clear Clear Turbid Turbid Lactescent
Xanthomas Eruptive Tendon,
tuberous
None Palmar,
tuberoeruptive
None Eruptive
Pancreatitis +++ 0 0 0 0 +++
Coronary
atherosclerosis
0 +++ +++ +++ +/– +/–
Peripheral
atherosclerosis
0 + + ++ +/– +/–
Molecular
defects
LPL and ApoC-II LDL receptor,
ApoB-100,
PCSK9, LDLRAP,
ABCG5 and
ABCG8
ApoC-III ApoE ApoA-V ApoA-V and
GPIHBP1
Genetic
nomenclature
FCS FH, FDB, ADH,
ARH,
sitosterolemia
FCHL FDBL FHTG FHTG

12. Classification:
• Primary Disorders of Elevated ApoB-Containing
Lipoproteins
 Lipid Disorders Associated with Elevated LDL-C and Normal
Triglycerides
 Elevated Plasma Levels of Lipoprotein(a)
 Lipid Disorders Associated with Elevated Triglycerides
• Inherited Causes of Low Levels of ApoB-Containing
Lipoproteins
• Genetic Disorders of HDL Metabolism
 Inherited Causes of Low Levels of HDL-C
 Inherited Causes of High Levels of HDL-C

13. Secondary forms of hyperlipidemia

14. Primary Disorders of Elevated ApoB
Containing Lipoproteins
Lipid Disorders Associated with Elevated LDL-C and
Normal Triglycerides
1. Familial Hypercholesterolemia (FH)
2. Familial Defective ApoB-100 (FDB)
3. Autosomal Dominant Hypercholesterolemia Due to
Mutations in PCSK9 (ADH-PCSK9 or ADH3)
4. Autosomal Recessive Hypercholesterolemia (ARH)
5. Sitosterolemia
6. Polygenic Hypercholesterolemia

15. Lipid Disorders Associated with Elevated LDL-C and Normal Triglycerides
LDL-C –apo B100
LDL RECEPTOR
LDL-RAP
CLATHRIN

16. Lipid Disorders Associated with Elevated LDL-C and Normal Triglycerides
Familial
hypercholesterolemia
[Class IIa]

17. Lipid Disorders Associated with Elevated LDL-C and Normal
Triglycerides-
Tendon
Xanthoma
Tuberous
Xanthoma

18. Why are statins not effective in receptor
negative homozygous FH ?

19. Primary Disorders of Elevated ApoB-Containing Lipoproteins
Familial Defective
ApoB-100 (FDB)

20. Primary Disorders of Elevated ApoB-Containing Lipoproteins
Autosomal Recessive
Hypercholesterolemia
(ARH)

21. Lipid Disorders Associated with Elevated LDL-C and Normal Triglycerides
• Autosomal Dominant
Hypercholesterolemia
Due to Mutations in
PCSK9 (ADH-PCSK9)

22. Lipid Disorders Associated with Elevated LDL-C and Normal Triglycerides
• Sitosterolemia/
Phytosterolemia
• Misshapen RBCs
• Megathrombocytes
• Hemolysis
• Gas chromatography
• Ezetimibe

23. Primary Disorders of Elevated ApoB
Containing Lipoproteins
Lipid Disorders Associated with Elevated
Triglycerides
1. Familial Chylomicronemia Syndrome
2. Apo A-V Deficiency
3. GPIHBP1 Deficiency
4. Familial Hypertriglyceridemia (FHTG)
5. Familial Combined Hyperlipidemia (FCHL)
6. Hepatic Lipase Deficiency
7. Familial Dysbetalipoproteinemia

24. Lipid Disorders Associated with Elevated Triglycerides

25. Lipid Disorders Associated with Elevated Triglycerides
Familial Chylomicronemia Syndrome (Type I Hyperlipoproteinemia;
Lipoprotein Lipase and Apoc-II Deficiency)

26. Clinical features
Lipemia Retinalis
Eruptive Xanthomas

27. Lipid Disorders Associated with Elevated Triglycerides
GPIHBP1 Deficiency ApoA-V Deficiency
Familial Hypertriglyceridemia (FHTG)
•Type IV hyperlipoproteinemia
•Type V hyperlipoproteinemia

28. Lipid Disorders Associated with Elevated Triglycerides
Hepatic Lipase Deficiency
Familial
Dysbetalipoproteinemia
(Type III
Hyperlipoproteinemia)

29. Paradoxes in Familial Dysbetalipoproteinemia
(Type III Hyperlipoproteinemia)
• Increased remnants
• High TAG
• Reduced LDL-C
• Increased CAD
VL

30. Lipid Disorders Associated with Elevated Triglycerides
Familial Combined Hyperlipidemia (FCHL) [Type IIb]

31. Inherited Causes of Low Levels of ApoB
Containing Lipoproteins
1. Abetalipoproteinemia
2. PCSK9 Deficiency
3. Familial
Hypobetalipoproteinemia (FHB)

32. Inherited Causes of Low Levels of ApoB Containing Lipoproteins
ApoB-48 Intestine Chylomicrons Structural protein for chylomicrons
ApoB-100 Liver VLDL, IDL, LDL,
Lp(a)
Structural protein for VLDL, LDL, IDL,
Lp(a). Ligand for binding to LDL receptor
Familial
Hypobetalipoproteinemia
(FHB)
Abetalipoproteinemia
[Bassen-Kornzweig
syndrome]

33. Abetalipoproteinemia [Bassen-Kornzweig syndrome]
Acanthocytes

34. Genetic Disorders of HDL Metabolism
Inherited Causes of Low Levels of HDL-C
1. Gene Deletions in the Apoav-AI-CIII-AIV Locus and Coding
Mutations in ApoA-I
2. Tangier Disease (ABCA1 Deficiency)
3. LCAT Deficiency
4. Primary Hypoalphalipoproteinemia
 Inherited Causes of High Levels of HDL-C
1. CETP Deficiency
2. Familial Hyperalphalipoproteinemia

35. Genetic Disorders of HDL Metabolism

36. Inherited Causes of Low Levels of HDL-C
• Gene Deletions in the
ApoAV-AI-CIII-AIV Locus
& Coding Mutations in
ApoA-I
• LCAT def.
• Corneal opacity
• CKD
• Hemolytic anemia

37. Inherited Causes of Low Levels of HDL-C
Diagnosis?? Tangier Disease

38. Inherited Causes of High Levels of HDL-C
CETP Deficiency
Familial
Hyperalphalipoproteinemia

39. Lp(a)

40. Management
• Investigations
• Treatment

41. Summary:
• Role of lipoproteins
• Elevated ApoB-Containing Lipoproteins
• Low Levels of ApoB-Containing Lipoproteins
• Disorders of HDL Metabolism
• Cardiovascular diseases
• Management

42. THANK YOU