Lecture 16: Chyonicron, VDL, LDL metabolism

Question 1

Discuss lipid transport in the blood by lipoproteins and
albumin.

Discuss the size and separations of lipoproteins.

Answer 1

Albumin
-Transports fatty acids through the blood by holding them in their hydrophobic pockets, which gets them through the water phase

Lipoprotein:

• Transports totally nonpolar TAGs (Triacylglycerals) and cholesteryl esters
• Phopholipid monolayer = outer shell thats polar and inside nonpolar that carries TAGs

Size/separation:

1) Ultra-Centrifugation
- Separates based on size and density
1) Chylomicrons –> Top
2) VLDL –> Very low density
3) IDL –> Intermediate density
4) LDL –> Low density
5) HDL –> High density

2) Protein electrophoresis:
- Separates based on overall charge (determined by apoproteins)

Question 2

Discuss chylomicron metabolism starting from formation to its uptake
into the liver.

Answer 2

1) Released by intertinal muscosal cells
2) Go into the lymph (contain dietary lipids and lipid soluable vitamins)

3) Join blood circulation
- Apo B-48
- Apo CII from HDL
- APO E from HDL

4) Cleaved by lipoprotein lipase

APO CII returns to HDL

5) Chylomicrons remnants are taken up by the liver
- APO B-48
- APO-E –> Needed for remnant receptors to let chylomicron remnants into the liver

Question 3

Describe the location and function of lipoprotein lipase in heart, skeletal muscle and fat.

Answer 3

Location:

• Capillaries of heart
• Muscle
• Adipose tissue

Function:

• Cleaves TAGs inside lipoproteins
• Released fatty acids enter the heart, muscle, fat cells for ENERGY METABOLISM

Question 4

Describe the conversion of VLDLs into IDLs by lipoprotein lipase and the uptake of IDL by the liver

Answer 4

Lipoproteins:
-Enzyme that cleaves TAGs in lipoproteins, shrinking microns and can go into the liver

Conversion VLDL –> IDLs:
-IDL’s formed in the blood by lipoprotein lipase from VDL
(VLD remnant = IDL)
-IDL’s travel around until they get close to liver
-50% IDL’s go in liver –> liver Capillaries and other half turns into LDL

Question 5

Describe the lipoproteins with the highest percentage of TAGs or of cholesteryl esters

Answer 5

• Chylomicrons contain the most TAGs, then VLDVL

- LDL’s contain the highest chloesterol

Question 6

Discuss the uptake of LDL into the liver and extra-hepatic tissues by receptor mediated endocytosis

Answer 6

-Formed in the blood and deliver cholesteryl esters to cells that need cholesterol, most LDL’s are taken up by the liver

Question 7

Describe the regulation of LDL-receptor synthesis.

Answer 7

1. The LDL receptor in the coated pit recognizes apo B-100 and binds LDL. Both are
   taken up by endocytosis. The clathrin coat is lost and an endosome is formed.
   The pH of the endosome allows the separation of LDL from its receptor. The LDL
   receptor can be recycled. The LDL is degraded to free cholesterol,
   fatty acids and amino acids.
2. The uptake of IDL and chylomicron remnants is performed in a similar fashion by a remnant receptor which recognizes apo E. The remnant receptor is also recycled.
3. A high cytosolic free cholesterol level activates ACAT (acyl CoA cholesterol
   acyl transferase) which forms a reservoir of cholesteryl esters.
4. If the cytosolic free cholesterol is still high then it inhibits the gene expressions
   of HMG CoA reductase and of the LDL receptor.
5. A low hepatic cytosolic free cholesterol level upregulates LDL-receptor synthesis.
   The increased uptake of LDL into the liver reduces the blood level of LDL.
   -This concept is used for treatment of hypercholesterolemia by statins and other drugs.

Question 8

Discuss the functions of deficiency of apo B-48, apo B-100, apo C-II and apo E, APO A

Answer 8

• Apo-lipid proteins that assemble chylomicrons and release them into the lymph
• Apo-B-48 –> needed to assemble of chylomicrons and their release into the lymph, Unique for intestinal epithelial cells = result of post transcriptional editing of the mRNA (Cytidine deaminase = stop codon so only half of mRNA of APO B gene)

-Apo-B-100 –> needed for synthesis and release of VLDLs into the blood and is
needed for recognition by the LDL-receptor. Apo B-100 oxidation in LDL leads to
oxLDL that enter macrophages which can lead to fatty streaks

-Apo-C-II –> provided for chylomicrons and VLDLs in the blood by HDLs. Apo C-II
activates lipoprotein lipase which cleaves TAGs in chylomicrons and VLDL

APO-E –> provided for chylomicrons and VLDLs in the blood by HDLs.
Apo E is needed for recognition by the hepatic remnant receptors and for the
uptake of chylomicron remnants and IDLs into the hepatocytes

APO-A–> needed for the reverse cholesterol transport of HDL

Question 9

Explain how oxidized LDL particles are formed and how they are involved with foam cell development and atherosclerosis

Answer 9

• Formed when there is too much LDL and don’t turnover as fast they can be oxidized and turn into OxLDL
• OxLDL is not recognized by the LDL-receptor. The scavenger receptor SR-A in macrophages allows uptake of oxLDL and leads to “ foam” cells that can release proinflammatory mediators

Question 10

What are the effects of deficiency of apo B-48, apo B-100, apo C-II and apo E

Answer 10

1) Apo B-48 deficiency:
- leads to low levels of chylomicrons as the assembly and release needs apo B-48.

2) Apo B-100 deficiency
-leads to low levels of VLDLs, IDLs and LDLs as the assembly and release of VLDLs needs apo B100.
(These deficiencies are found in abetalipoproteinemia (with MTP deficiency) and in
hypobetalipoproteinemia (loss of functional apo B).

3) Apo E deficiency:
-leads to high levels of chylomicron remnants and IDLs as the hepatic remnant receptors needs apoE for endocytosis.
(This is found in Hyperlipoproteinemia Type III (Dysbetalipoproteinemia).

4) Apo C-II deficiency leads to high levels of chylomicrons and VLDLs as apo C-II is needed for activation of lipoprotein lipase.
(This is found in Hypertriacylglycerolemia as seen in hyperlipoproteinemia Type I, IV and V. )