1. Cholesterol and Lipoproteins

2. Theme: Chest Pain

3. Objectives
1- Lipoproteins characteristics (Structure and Composition) 2- Metabolism of Lipoproteins Chylomicrons, HDL, LDL, IDL, vLDL and HDL) including regulatory mechanisms 3- Lipoprotein receptors and receptor mediated endocytosis 4- Transport of Cholesterol by Lipoproteins 5- Biochemical aspects of Atherosclerosis

4. LIPOPROTEINS
spherical particles with a hydrophobic core (TG and esterified cholesterol)
apolipoproteins on the surface
large: apoB (b-48 and B-100)
smaller: apoA-I, apoC-II, apoE
classified on the basis of density and electrophoretic mobility (VLDL; LDL; IDL;HDL;

5. Composition and properties of human lipoproteins
Lipoprotein class
Density (g/mL)
Diameter (nm)
Protein % of dry wt
Phospholipid %
Triacylglycerol % of dry wt
HDL
5 – 15 33 29 8
LDL
1.019 – 1.063
18 – 28 25 21 4
IDL 18 22 31
VLDL
0.95 – 1.006 10 50
chylomicrons
< 0.95
1 - 2 7 84
Composition and properties of human lipoproteins
most proteins have densities of about 1.3 – 1.4 g/mL and lipid
aggregates usually have densities of about 0.8 g/mL

6. Lipoprotein structure

7. The apolipoproteins major components of lipoproteins
often referred to as aproteins
classified by alphabetical designation (A-E)
the use of roman numeral suffix describes the order in which the apolipoprotein emerge from a chromatographic column
responsible for recognition of particle by receptors

8. Apoproteins of human lipoproteins
A-I (28,300)- principal protein in HDL
90 –120 mg% in plasma; activates LCAT
A-II (8,700) – occurs as dimer mainly in HDL
30 – 50 mg %; enhances hepatic lipase activity
B-48 (240,000) – found only in chylomicron
<5 mg %; derived from apo-B-100 gene by RNA editing; lacks the LDL receptor-binding domain of apo-B-100
B-100 (500,000) – principal protein in LDL
80 –100 mg %; binds to LDL receptor

9. Apoproteins of human lipoproteins
C-I (7,000) – found in chylomicron, VLDL, HDL
4 – 7 mg %; may also activate LCAT
C-II (8,800) - found in chylomicron, VLDL, HDL
3 – 8 mg %; activates lipoprotein lipase
C-III (8,800) - found in chylomicron, VLDL, IDL, HDL
8 15 mg %; inhibits lipoprotein lipase
D (32,500) - found in HDL
8 – 10 mg %; also called cholesterol ester transfer protein (CETP)
E (34,100) - found in chylomicron, VLDL, IDL HDL
3 – 6 mg %; binds to LDL receptor
H (50,000) – found in chylomicron; also known as b-2-glycoprotein I (involved in TG metabolism)

10. Major lipoprotein classes
Chylomicrons (derived from diet)
density <<1.006
diameter nm
dietary triglycerides
apoB-48, apoA-I, apoA-II, apoA-IV, apoC-II/C-III, apoE

11. Chylomicron Synthesis , RER-Golgi (Apo-B-48, cytosine to uracil)
Assembly, enzymes in SER, (microsomal triacylglycerol transfer protein, MTP)
Modification of nascent chylomicron , addition of apo-E and apo-CII source is HDL, (necessary for activation of Lipo-protein lipase)
LPL regulation, Km large in adipose, small in heart (energy requirement of heart muscle…)
Chylomicron remnants, less TAG, -apoC, apoE for receptor binding in liver, receptor mediated endocytosis.

12. Cholesterol and lipid transport Chylomicrons

13. Major lipoprotein classes
VLDL
density >1.006
diameter nm
endogenous triglycerides
apoB-100, apoE, apoC-II/C-III
formed in the liver as nascent VLDL (contains only triglycerides, apoE and apoB)

14. VLDL
nascent VLDLs interact with HDL to generate mature VLDLs (with added cholesterol, apoC-II and apoC-III)
mature VLDLs are acted upon by LpL to generate VLDL remnants (IDL)
IDL are further degraded by hepatic triglyceride lipase (HTGL) to generate LDLs

15. Major lipoprotein classes
IDL (intermediate density lipoproteins)
density:
diameter: nm
cholesteryl esters and triglycerides
apoB-100, apoE, apoC-II/C-III

16. Major lipoprotein classes
LDL (low density lipoproteins)
density:
diameter: 18-25nm
cholesteryl esters
apoB-100
< 130 LDL cholesterol is desirable, is borderline high and >160 is high

17. Metabolism of LDL Receptor mediated endocytosis
High cholesterol due to LDL function has following consequences
Inhibition of HMG COA reductase
LDL receptor synthesis inhibition (transcription…)
ACAT
Chemically modified LDL (macrophage scavenger receptors SR-A, accumulation in macrophages----foam cells-atherosclerosis

18. The LDL receptor
characterized by Michael Brown and Joseph Goldstein (Nobel prize winners in 1985)
based on work on familial hypercholesterolemia
receptor also called B/E receptor because of its ability to recognize particles containing both apos B and E
activity occurs mainly in the liver
receptor recognizes apo E more readily than apo B-100

19. Representation of the LDL receptor (839 aa)
extracellular domain is
responsible for apo-B-100/apo-E binding
intracellular domain is
responsible for clustering of LDL
receptors into coated
pit region of plasma
membrane

21. Major lipoprotein classes
HDL (high density lipoproteins)
density:
diameter: 5-12nm
cholesteryl esters and phospholipids
apoA-I, apoA-II, apoC-II/C-III and apoE

22. HDLs Several subfamilies exist
Discoidal HDL :
contains cholesterol, phospholipid, apoA-I, apoA-II, apoE and is disc shaped;
it is formed in liver and intestine
It interacts with chylomicron remnants and lecithin-cholesterol acyl transferase (LCAT) to form HDL3

23. HDLs
HDL3
composed of cholesterol, cholesterol ester, phospholipid and apoA and apoE
interacts with the cell plasma membranes to remove free cholesterol
reaction with LCAT converts HDL3 to HDL2a (an HDL with a high apoE and cholesterol ester content)
cholesterol ester-rich HDL2a is then converted to triglyceride-rich HDL2b by concomitant transfer of HDL cholesterol esters to VLDL and VLDL triglycerides to HDL with the help of CETP

24. Functions of HDL transfers proteins to other lipoproteins
picks up lipids from other lipoproteins
picks up cholesterol from cell membranes
converts cholesterol to cholesterol esters via the LCAT reaction
transfers cholesterol esters to other lipoproteins, which transport them to the liver (referred to as “reverse cholesterol transport)

25. Reverse Cholesterol Transport
Inverse relation ship between plasma HDL and atherosclerosis
Efflux of cholesterol from periphery to HDL (ABCA1),
Esterification by LCAT,
binding of HDL2 (rich in cholesterol esters) to liver and steroidogenic cells,
transfer of cholesterol to these cells
release of lipid depleted HDL3

26. Lipoproteins (a)- Lp(a)
another atherogenic family of lipoproteins(at least 19 different alleles)
they consist of LDL and a protein designated as (a)
the apoA is covalently linked to apoB-100 by a disulfide linkage
unusual in that it contains a kringle protein motif/domain (tri-looped structure with 3 intramolecular disulfide bonds
Large amounts in plasma are associated with high risk association with premature coronary artery disease and stroke
Elevated level slows breakdown of blood clot.
Similar to plasminogen, competes with it for binding with fibrin

27. Atherosclerosis
hardening of the arteries due to the deposition of atheromas
heart disease is the leading cause of death
caused by the deposition of cholesteryl esters on the walls of arteries
atherosclerosis is correlated with high LDL and low HDL

28. Frederickson -WHO classification
Type I: incr. chylomicrons, reduced HDL, absence of lipoprotein lipase; deficiency of apo CII (hyperchylomironemia)
Type II-A: raised LDL; decreased catabolism of LDL (receptor deficiency or polygenic)
Type II-B: raised VLDL + LDL; often reduced HDL; increased production of VLDL + impaired LDL catabolism
Type III: raised IDL (dysbetalipoproteinemia); abnormal apolipoprotein E; impaired catabolism of IDL; elevated cholesterol and triglycerides (formerly known as broad beta disease)

29. Frederickson -WHO classification
Type IV: raised VLDL; often reduced HDL; impaired VLDL catabolism; dietary indiscretion ( formerly known as hyperprebetalipoproteinemia)
Type V: raised chylomicrons + VLDL; reduced HDL; reduced lipoprotein lipase + VLDL hypersecretion (formerly known as mixed lipemia)

30. Disorders of Cholesterol and Lipoproteins in 3 Categories
Specific Familial/Genetic Disorders
These comprise a small minority of patients
Secondary to other Diseases
Diabetes, Hypothyroid, Nephrotic syndrome, Renal Failure, Lupus
Dietary/Polygenic --(most common)
This is the great majority of patients with elevated cholesterol/LDL

31. Thank You