Chylomicrons, VLDL and LDL Mediastinum

Question 1

How are lipids transported in blood?

Answer 1

Albumin binds free fatty acids in hydrophobic pockets

Lipoproteins-the purpose of lipoproteins is to transport the totally nonpolar TAGs and cholesteryl esters

Question 2

What is special about the structure of lipoproteins?

Answer 2

1. Lipoproteins are spherical complexes of lipids that interact on the outside with the water phase and transport nonpolar lipids inside the lipoprotein structure
2. The outer shell is a phospholipid monolayer which makes only the outside polar and keeps the inside hydrophobic for transport of TAGs and cholesteryl esters
3. The phospholipid monolayer contains apo(lipo)proteins and a small amount of free cholesterol

Question 3

How are plasma lipoproteins separated?

Answer 3

Lipoproteins can be separated with twin different methods:
1. Ultra-Centrifugation: regarding their size and density

2. Protein electrophoresis: regarding their overall change determined by apo proteins

Question 4

Separation by ultra-Centrifugation from very low to high density leads to…

Answer 4

Naming as:

1. Chylomicrons- are separated without Centrifugation as they float on top of a blood sample
2. VLDL (Very low density lipoproteins)
3. IDL (Intermeduate density lipoproteins)
4. LDL(low density lipoproteins)
5. HDL (high density lipoproteins)

Question 5

Lipoproteins have different sizes…

Answer 5

Chylomicrons are the largest and contain mostly TAGs.

VLDLs are TAG rich and LDLs are cholesterol rich.

HDLs are the smallest and rich in apo-proteins

Question 6

What are the functions of chylomicrons ?

Answer 6

Released by the intestinal mucosal cells into the lymph and contain depieaptary lipids including soluble vitamins. They join later the blood circulation and their TAGs are cleaved by lipoprotein lipases. The chylomicrons remnants are only taken up by the liver

Question 7

What are the functions of VLDLs?

Answer 7

Released ve the liver into the blood and contain endogenous TAGs and cholesteryl esters. Lipoprotein lipases cleave the TAGs and the VLDL remnant are called IDL. Half of the IDLs are taken up into the liver and the other half is used to form LDLs

Question 8

What is the function of LDLs?

Answer 8

Are formed in the blood and deliver cholesterol esters to cells that need cholesterol. Most LDLs are taken up by the liver

Question 9

What are the functions of HDLs?

Answer 9

Perform the reverse cholesterol transport to the liver and are filled in the blood with cholesteryl esters. HDL prov7de the apolipoproteins apo CII and apo E to chylomicrons and VLDLs

Question 10

Describe chylomicrons formation and release

Answer 10

1. Intestinal epithelial cells form chylomicrons containing dietary lipids and release these big lipoproteins into the lymph
2. Assembly of the apo B-48 with lipids inside the cells needs MTP (Microsomal TAG transfer protein)
3. Both apo B-48 and MTP are needed for the release of chylomicrons into the lymph

Question 11

How is apo B- 48 synthes8zed?

Answer 11

Post transcriptional editing of the mRNA

Unique for intestinal cells

Cytidine deaminase forms the stop codon UAA leading to translation of only 48% of the mRNA of the apo B gene

Question 12

Explain the metabolism of chylomicrons

Answer 12

• Dietary TAGs aren’t meant to be stored in intestinal mucosal cells where chylomicrons (CM) are formed. Apo 48 and MTP are needed for the assembly and the release of nascent chylomicrons in the lymph (not into the hepatic vein ). Chylomicrons contain mainly dietary TAGs and dietary cholesteryl esters as well as lipid-soluble vitamins and will join the blood circulation at the thoracic duct into thr subclavian vein
• Once in the blood chylomicrons collide with HDLs which contain apo E and apo CII and these apolipoproteins are rubbed into the chylomicrons membrane
• In the blood chylomicrons have the purpose to transport dietary lipids and to provide substrates for lipoprotein lipases which need CII for activation
• Lipoprotein lipases are mainly anchored in capillaries of heart, muscle and adipose tissue and they cleave TAGs in lipoproteins and generate free fatty acids, glycerol, and a lipoprotein that is now smaller in size (a remnant). Apo CII is given back to HDL
• Chylomicrons remnants are formed which contain apo 48 and apo E. They have the function to deliver the dietary cholesteryl esters, lipid-soluble vitamins and some TAGs to the liver.
• They are only taken up into the liver by specific hepatic remnant receptors that allow endocytosis: fir this process apo E is needed.

Question 13

Where is lipoprotein lipase found and function?

Answer 13

Thus enzyme is anchored in capillaries of heart, muscle and adipose tissue and cleaves TAGs inside of lipoproteins. The released fatty acids enter the heart, muscle and fat cells

LPL acts in the blood and needs activation by apo C-II which it finds in chylomicrons and VLDL

Question 14

Where are the largest amounts of lipoprotein lipases found?

Answer 14

Largest amount found in capillaries

The well-oxygenated heart uses always fatty s I’d degeneration fir its energy metabolism

Question 15

What is special in lipoprotein lipase in fat tissue?

Answer 15

In fat tisssue, it is insulin-dependent

Insulin is needed for activation of lipoprotein lipase which cleaves TAGs in the blood and generates freee fatty acids that can be stored as TAGs inside the fat cells.

Question 16

Explain the metabolism of VLDL, IDL & LDL

Answer 16

-VLDLs are formed in hepatocytes and contain endogenous lipids. TAGs represent about 60% of VLDLs and are grouped as “TAG-rich” lipoproteins. The nascent VLDLs released by hepatocytes contain only apo B-100. HDL adds during collision apo C and apo E which leads to functional VLDLs.

One purpose of VLDLs released from the liver is to prevent TAG accumulation in hepatocyte and to provide substrates for lipoprotein lipase resulting in fatty acids fir other cells. In heart cells fatty acids are used fir energy metabolism, in fat cells they are stored in form of TAGs dependent upon insulin.

-After cleavage of some TAGs by lipoprotein lipase, the remnant of VLDL (IDL) is formed. About half of the IDLs are taken up into the liver via the remnant receptor (apo E is needed). The remaining IDLs provide TAGs for hepatic lipase which is found anchored in hepatic capillaries. LDLs are formed that need apo B 100 fir uptake with the LDL- receptor

The purpose of LDL is to transport cholesteryl esters and deliver cholesterol to cells that need it for their plasma membranes or for steroid hormone synthesis. LDLs contain apo B100 and can be endocytosed by a receptor-mediated process in the liver or peripheral cells. About 70% of the newly formed LDL are taken up into liver

LDLs can be modified and oxidized creating oxLDLs especially at apo B100. The oxLDLs are not recognized by the LDL receptor but will enter macrophages via SR-A receptors which eventually lead to foam cells

Question 17

Contrast lipoprotein lipase and hepatic lipase

Answer 17

IDL & LDL are formed in blood

Lipoprotein (LPL) forms IDL from VLDL

Hepatic lipase (HTGL) forms LDL from IDL

1. TAGs in VLDLs- are cleaved by lipoprotein which is anchored in capillaries of heart, muscle and fat tissue and forms IDL
2. TAGs in IDLs-are cleaved by hepatic lipase which is anchored in hepatic capillaries and forms LDL

Question 18

Which lipoproteins have the highest percentages of TAGs, cholesterol and proteins?

Answer 18

Chylomicrons have the highest % of TAAGs. They contain dietary lipids (exogenous source)

VLDLs follow with a high TAG %
They contain hepatic lipids (endogenous source)

LDLs have the highest % of cholesterol
They contain hepatic lipids from VLDL

HDLs have the highest % of protein
They act as reservoir for apoproteins

Question 19

What is the significance of HDLs having apoproteins?

Answer 19

HDLs contain many apoproteins

It provides apo CII and apo E to chylomicrons and VLDLs. It keeps apo A for its reserve cholesterol transport

Question 20

Explain regulation of LDL uptake and of cholesterol synthesis.

Answer 20

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 (Acetyl 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 up regulates LDL-receptor synthesis. The increased uptake of LDL into the liver reduces the blood level of LDL.
   This concept is used in treatment of hypercholesterolemia by statins and other drugs

Question 21

How do dietary cholesterol reduces hepatic LDL-receptors?

Answer 21

• In the liver especially after a cholesterol rich meal the uptake of chylomicron remnants lead to high free cytosolic cholesterol levels which reduce LDL-receptor synthesis
• This leads to temporary increased levels of serum LDL
• Once the dietary cholesterol is used and the cytosolic amount is reduced: then the LDL- receptor synthesis take place again and LDL blood levels decrease

Question 22

What does apo-b 48 deficiency lead to?

Answer 22

Low levels of chylomicrons as the assembly and release needs apo B-48

Question 23

How does apo B- 100 deficiency affect the b9dy?

Answer 23

Leads to low levels of VLDLs, IDLs, and LDLs as the assembly and release of VLDLs needs apo B 100

These deficiencies are found in abetalipoproteinemia ( with MTP deficiency) and in hypobetalipoproteinemia (loss of functional apo B)

Question 24

How does Ape E deficiency affect the body?

Answer 24

Leads to high levels of chylomicrons remnants and IDLs as the hepatic remnant receptors needs apo E for endocytosis
This is found in Hyperlipoproteinemia Type III (Dysbetalipoproteinemia)

Question 25

What does Apo C-II deficiency lead to?

Answer 25

Leads to high levels of chylomicrons and VLDLs as apo C-II is needed for activation of lipoprotein lipase.

This is found in Hypertriacylglyceremia as seen in hyperlipoproteinemia Type I, IV and V

Question 26

What is the significance of oxLDL?

Answer 26

LDL is modified to oxLDL

OxLDL is not recognized by the LDL receptor SR-A in macrophages allows uptake of oxLDL and leads to “foam cells” that can re,ease pro inflammatory mediators

Question 27

How do High LDL & oxLDL increase risk of atherosclerosis?

Answer 27

Fatty streaks contain smooth muscle cells and macrophages (foam cells) filled with oxLDL

Fibrofatty atheroma shows smooth muscle proliferation, collagen and lipid debris from destroyed foam cells

Question 28

Outline chylomicron metabolism

Answer 28

Chylomicrons are filled in intestinal mucosal cells with dietary lipids and released into the lymph. This needs apo B48 and MTP. The chylomicrons will eventually join the blood circulaation

The dietary TAGs in chylomicrons are cleaved mostly in capillaries of the heart and adipose tissue by lipoprotein lipases that need apo CII for activation.

The formed free fatty acids will be used for energy metabolism in heart and muscle or are stored in fat cells as TAGs

Only the chylomicron remnants containing less TAGs and mainly cholesteryl esters but also the lipid-soluble vitamins are taken up by the liver by remnant receptors (need apo E) and endocytosis

Question 29

Outline of VLDL metabolism

Answer 29

VLDLs are filled in hepatocyte with endogenous TAGs and cholesteryl esters and released into the blood (apo B-100 and MTP)

The TAGs in VLDL are cleaved mostly in capillaries of the heart and fat tissue by lipoprotein lipases which need apo CII for activation

The formed free fatty acids will be used for energy in the heart and skeketal muscle or are stored in fat cells as TAGs. The remnants of VLDLs are IDL

IDLs are either taken up by the liver (apo E, remnant receptors or are used to for, blood