Disorders of Lipoprotein Metabolism

Comprehensive description of various primary dyslipidemias, cholesterol transport and molecular mechanisms involved.
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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

10. 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 +++ +++ Coronary atherosclerosis +++ +++ +++ +/– +/– Peripheral atherosclerosis + + ++ +/– +/– 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

11. 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

12. Secondary forms of hyperlipidemia

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

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

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

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

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

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

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

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

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

22. Primary Disorders of Elevated ApoB Containing Lipoproteins Lipid Disorders Associated with Elevated Triglycerides Familial Chylomicronemia Syndrome Apo A-V Deficiency GPIHBP1 Deficiency Familial Hypertriglyceridemia (FHTG) Familial Combined Hyperlipidemia (FCHL) Hepatic Lipase Deficiency Familial Dysbetalipoproteinemia

23. Lipid Disorders Associated with Elevated Triglycerides

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

25. Clinical features Lipemia Retinalis Eruptive Xanthomas

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

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

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

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

30. Inherited Causes of Low Levels of ApoB Containing Lipoproteins Abetalipoproteinemia PCSK9 Deficiency Familial Hypobetalipoproteinemia (FHB)

31. 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]

32. Abetalipoproteinemia [ Bassen-Kornzweig syndrome] Acanthocytes

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

34. Genetic Disorders of HDL Metabolism

35. 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

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

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

38. Lp (a)

39. Management Investigations Treatment

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

41. THANK YOU