1. Lipoprotein
Structures, Function and Metabolism
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2. Lecture Outline What are lipoproteins? What do they do?
Basic structure of lipoproteins
Lipoprotein metabolism
Hyperlipoproteinemia
Cholesterol and bile acid metabolism
Role of lipoproteins in atherosclerosis

3. What are lipoproteins?
Molecular complexes that consist of lipids and proteins. They function as transport vehicles for lipids in blood plasma.
Lipoproteins deliver the lipid components (cholesterol and triglyceride etc.) to various tissues for utilization.
Inner droplet of neutral (water-insoluble core lipids); primarily triglycerides and cholesteryl esters
A solubilizing surface layer of phospholipids and unesterified cholesterol
Specific proteins (apolipoproteins) attached to the outer lipid layer through their specific lipophilic domains

4. Hydrophobic lipids
Amphiphilic lipids

5. In phospholipids X=

6. Structure of lipoprotein
Hydrophobic lipids (TG, CE) in the core
Amphiphilic lipids (C, PL) and proteins on the surface

7. Classification of plasma lipoproteins according to their density
Chylomicron (CM)
Very low density lipoprotein (VLDL)
Intermediate density lipoprotein (IDL)
Low density lipoprotein (LDL)
High density lipoprotein (HDL)

8. Lipoproteins
Each contains different kinds and amounts of lipids and proteins
The more protein, the higher the density
The more lipid, the lower the density
Each has different function

9. Characteristics of human plasma lipoproteins
CM VLDL LDL HDL
Density (g/mL) <
Diameter (nm)
Apolipoprotein A,C,E,B A,C,E,B B A,C,D,E
Composition (%)
Proteins
Lipids
Lipid composition (%) TG
CE+C PL
Free fatty acid

10. Classification of plasma lipoproteins according to
their electrophoretic mobility
(CM)
1967, Fredrickson et al.
a-lipoprotein (HDL)
Pre-b-lipoprotein (VLDL)
b-lipoprotein (LDL) CM

11. Important enzymes and proteins involved in lipoprotein metabolism

12. LPL (Lipoprotein Lipase)
Locate in extracellular on the walls of
blood capillaries, anchored to the endothelium.
Hydrolyze triglyceride (TG) in the core of
CM and VLDL to free fatty acids and glycerol.
The free fatty acids are transported into the
tissue, mainly adipose, heart, and muscle (80%),
while about 20% goes indirectly to the liver.

14. HL (Hepatic Lipase) Bound to the surface of liver cells,
Hydrolyzes TG to free fatty acids and glycerol
Unlike LPL, HL does not react readily with
CM or VLDL but is concerned with TG
hydrolysis in VLDL remnants and HDL metabolism

15. (Lecithin:Cholesterol Acyltransferase)
LCAT
(Lecithin:Cholesterol Acyltransferase)
Formation of cholesterol esters in lipoproteins

16. CETP
(Cholesterol Ester Transfer Protein)

17. Apolipoproteins Act as structural components of lipoproteins
Recognize the lipoprotein receptors on cell membrane surface as ligand
Activate/inhibit enzymes involved in lipoprotein metabolism

18. Apo AI: Activator LCAT
Apo AII: Inhibitor of hepatic lipase (HL)
Apo A-IV: Activator of LCAT
Apo B-100 (liver, 4564 Aa): structure, ligand
Apo B-48 (intestine, 2152Aa): structure
Apo C-I : Activator of LCAT
Apo C-II: Activator of LPL
Apo C-III: Inhibitor of LPL
Apo D: Function unknown
Apo E: Ligand

19. In liver
In intestine
ApoB100 and ApoB48 come from same gene

20. What do lipoproteins do?
Serve to transport lipids and lipid-soluble compounds between tissues and organs
Substrates for energy metabolism (TG)
Essential components for cells (PL, C)
Precursors for hormones (C)
Lipid soluble vitamins
Precursors for bile acids (C)

21. Metabolism of chylomicrons
Surface Monolayer Phospholipids
Free Cholesterol
Protein
Hydrophobic Core Triglyceride
Cholesteryl Esters

22. Metabolism of chylomicrons
Transport dietary TG and Cholesterol from the intestine to the peripheral tissues
The dietary TG are first acted by intestine lipase and absorbed as monoacylglycerol, fatty acid and glycerol. Within the intestine cells, they are resynthesized into TG.
CM are synthesized in the intestine using TG, PL, C, ApoB48, and ApoAs and secreted into the lymph and reach blood through thoracic duct.
Nascent CM pick up apoE, apoCs and some apoAs from HDL.

23. Metabolism of chylomicrons
In the capillaries of peripheral tissue, lipoprotein lipase (LPL) degrades triglycerol (TG) of chylomicrons to fatty acids (FA) and glycerol which enter tissues by diffusion
Lipoprotein lipase (LPL) is activated by apo C-II
After most of the TG is removed, chylomicrons become chylomicron remnants. During the process, CM give apoC and apoA to HDL

24. Metabolism of chylomicrons
CM remnants bind to specific receptors on the surface of liver cells through apo E and then the complex is endocytosed.
remnant receptor or
apoE receptor or
LRP (LDL receptor-related protein)
Chylomicron remnants deliver dietary cholesterol and some cellular cholesterol (via HDL) to the liver.
Half life of CM is short, less than 1 hour.

25. Metabolic fate of chylomicrons
Metabolic fate of chylomicrons. (A, apolipoprotein A; B-48, apolipoprotein B-48; , apolipoprotein C; E, apolipoprotein E; HDL, high-density lipoprotein; TG, triacylglycerol; C, cholesterol and cholesteryl ester; P, phospholipid; HL, hepatic lipase; LRP, LDL receptor-related protein.) Only the predominant lipids are shown.

26. Metabolism of VLDL and LDL

27. VLDL
VLDL are made by liver. Liver synthesizes TG and cholesterol and packages them into VLDL for export into blood.
Most lipid in the core of VLDL is triglyceride
Nascent VLDL contain apoB100. In blood nascent VLDL pick up apoE and apoCs from HDL and become matured VLDL.

28. VLDL
In the capillaries of various tissues, LPL degrades TG to fatty acids and glycerol, which enter the tissues by diffusion. ApoC-II is needed in this step to activate LPL.
When VLDL loses triglyceride, it transforms into VLDL remnant, also named as IDL (intermediate-density lipoprotein).
During the process, some apolipoproteins (apo As and apoCs) are transferred back to HDL.
VLDL function: Deliver TG from liver to peripheral tissue cells.

29. Fates of VLDL remnants (IDL)
Results from loss of TG in VLDL
Contains relatively more cholesterol esters
Taken up by liver or transform into LDL
1) A proportion of the VLDL remnant (IDL) is taken up by liver through the LDL receptor (apoE-mediated).
2) The other remnant is further acted upon by hepatic lipase (HL) and converted into LDL. LDL loses all apolipoproteins except apoB100.

30. LDL Most core lipid in LDL is cholesterol ester.
Major cholesterol carrying lipoprotein
2/3 - 3/4 of serum cholesterol is carried by LDL
50% of mass is cholesterol
Produced as a product of VLDL metabolism
Delivers cholesterol to peripheral tissues for biosynthesis and steroid hormone production
Most core lipid in LDL is cholesterol ester.
ApoB100 is only apolipoprotein in the surface.

31. LDL receptor Also named as apoB-100/apoE receptors
LDL receptors exist in the liver and in most peripheral tissues
The complexes of LDL and receptor are taken into the cells by endocytosis, where LDL is degraded but the receptors are recycled
LDL cholesterol levels are positively related to risk of cardiovascular disease
Therefore, cholesterol in LDL has been called “bad cholesterol”