5C- Cholesterol metabolism

Question 1

How does dietary cholesterol get into our intestine epithelia?

Answer 1

Micelles

Question 2

What happens to the cholesterol after it is absorbed into the intestinal epithelium by micelles?

Answer 2

It’s either put into chylomicrons and transported to the lymph or it’sjust put back into the intestinal lumen

Question 3

All 27 carbons of cholesterol are derived from what molecule?

Answer 3

Acetyl CoA

Question 4

What is the first and the rate limiting step of cholesterol synthesis?

Answer 4

The conversion of acetyl-coA’s into mevalonate

Question 5

After mevalonate is made, what is the next step in cholesterol synthesis? What is used?

Answer 5

mevalonate is converted into 2 isoprenes using 3 ATP

Question 6

After the isoprenes are formed, what is the next step in cholesterol synthesis?

Answer 6

Condensation of six activated 5-carbon isoprenes to form the 30-Carbon Squalene

Question 7

After the squalene is formed, what is the next step in cholesterol synthesis?

Answer 7

conversion of the squalene into the 4 ringed cholesterol molecule

Question 8

What enzyme is the rate limiting enzyme of choleterol synthesis? What does it do?

Answer 8

HMG-CoA reductase. It converts HMG-CoA to mevalonate in the first step of cholesterol synthesis

Question 9

How is HMG-CoA reductase regulated by insuling and glucagon?

Answer 9

Glucagon causes the phosphorylation of it, inactivating it. Insulin causes the dephosphorylation of it, activating it.

Question 10

What is the relationship between SREBP and HMG-CoA reductase transcription?

Answer 10

SREBP is a sterol that increases the rate of transcription of genes required for HMG-CoA reductase expression by binding to the sterol regulatory element of the gene. SREBP is activated by the proteases SCAP and S2P. When sterol levels rise, SCAP is deactivated and this will stop HMG CoA reductase gene transcription.

Question 11

What are cholesterol esters used for?

Answer 11

used for making cell membranes, forming steroid hormones and biosynthesis of vitamin D

Question 12

What are bile acids used for?

Answer 12

used to emulsify fats in the small intestine because they have polar and nonpolar ends

Question 13

What is biliary cholesterol?

Answer 13

free cholesterol that enters the gut lumen via the biliary tract

Question 14

What is ACAT?

Answer 14

ACAT = acyl-CoA-cholesterol acyl transferase
It catalyzes the transfer of a fatty acid from fatty acyl CoA to the hydroxyl group of a cholesterol molecule in the cell.

Question 15

What is the role of 7α-hydroxylase in the synthesis of bile salts from cholesterol?

Answer 15

7α-hydroxylase is the rate limiting step in the creation of bile salts from cholesterol, and it is inhibited by bile salts. ie: when the reaction produces bile salts, these salts in turn stop the reaction from producing more bile salts

Question 16

When 3 carbons are removed from side chains of cholesterol, what 2 bile salts are created?

Answer 16

Chenocolic acid and colic acid

Question 17

What do intestinal bacteria do to bile salts?

Answer 17

Intestinal bacteria deconjugate and dehydroxylate some of these primary bile salts by removing the glycine or taurine that was added during conjugation. This makes those bile salts, secondary bile salts and they are less likely to be reabsorbed.

Question 18

What types of apoproteins are on chylomicrons?

Answer 18

ApoB-48, ApoC, ApoE

Question 19

What types of apoproteins are on VLDL?

Answer 19

ApoB-100, ApoC, ApoE

Question 20

What types of apoproteins are on IDL?

Answer 20

ApoC, ApoE

Question 21

What types of apoproteins are on HDL

Answer 21

ApoA, ApoC, ApoE

Question 22

How does cholesterol get transported by VLDL?

Answer 22

when fatty acids exceed the amount needed by the liver, they are turned into TGs and packaged with apoproteins to make VLDL. As VLDL they can travel to sites that can use them like skeletal muscle, cardiac muscle, adipose tissue and milk production. When it reaches its target, ApoC activates lipoprotein lipase which hydrolyses the triacylglycerol. This causes the release of the fatty acids and glycerol of the VLDL, which is taken up by the tissue. Half of the remnants of the VLDL are then taken back up by the liver using ApoE, while the other half become IDL

Question 23

How does cholesterol get transported by IDL?

Answer 23

VLDL remnants that still have some triacylglycerol’s attached. Can either be taken up by the liver or converted to LDL by hepatic triglyceride lipase.

Question 24

How does cholesterol get transported by LDL?

Answer 24

60% is taken back into liver using ApoB-100. The other 40% are taken to gonadal cells and adrenocortical cells that also have ApoB-100 receptors, and are used to make steroid hormones, Vitamin D and cell membranes. Macrophages destroy any remaining LDL particles, and the immune response could cause atherosclerosis.

Question 25

What is the function of the LCAT?

Answer 25

HDL can remove cholesterol from cells, but it needs the LCAT enzyme to trap the cholesterol in the HDL particle. LCAT will convert the cholesterol into a cholesterol ester in the HDL to trap it. It does this by transferring a fatty acid from a lecithin molecule to the cholesterol.

Question 26

How does LDL enter the cell?

Answer 26

The receptors for LDL are found on cell membranes in areas called coated pits, which contain the protein clathrin. The receptor-LDL complex is taken into the cell within a vesicle, and is then broken down by lysosomal enzymes. It is reesterified by ACAT to prevent potential damage to the cell membrane.

Question 27

What is the role of HDL particles for VLDL particles?

Answer 27

HDL can give ApoC and ApoE to chylomicrons and VLDL making them mature. After the chylomicrons and VLDL are digested, the proteins are picked back up by HDL.

Question 28

What is HDL’s role as the reverse cholesterol transporter?

Answer 28

Reverse cholesterol transport is the ability of HDL to remove cholesterol from cells and bring them to the liver. The protein ABC1 in cells helps move cholesterol out of the cell using ATP, where is can go into HDL. Its trapped in HDL by LCAT and transported to the liver.

Question 29

What would happen if there is a defect in LDL receptors?

Answer 29

If because of some mutation, LDL can not be taken into cells because of defective or too few receptors, LDL levels will be high in the blood. This will prevent negative feedback for cholesterol synthesis in the cell, so cholesterol production in the cells will increase as well. The LDL in the blood may deposit in vascular walls. Macrophages will take in these lipids, but become engorged and get stuck in the subendothelial space of the blood vessel, and may develop into an atherosclerotic plaque.

Question 30

How does atherosclerosic plaques form?

Answer 30

Insult to endothelial cells (can be too much LDL, too little HDL, smoking etc.)  monocytes are signaled to enter site of injured endothelial cells  Monocytes are converted to macrophages and are attracted to enter the subintimal space by cytokines  the macrophages multiply and take in modified fatty acids from LDL and become foam cells, causing the appearance of the “fatty streak”  separations in endothelial cells for blood and platelets  platelets secrete cytokines that perpetuate the process and increase the chance for a clot  fibrous cap forms over and bulges into the lumen causing some stenosis  smooth muscle secretes plaque matrix material and thin the fibrous cap  cap ruptures and plaque contents meet with procoagulant elements in the circulation  acute thrombus formation (blood clot) which can cause an infarction.

Question 31

What is the problem with elevated Lp(a)?

Answer 31

Lipoprotein A [Lp(a)] inhibits normal clot busting which can lead to thrombus formation. It is independent of blood cholesterol levels.

Question 32

What is the mechanism of action of statin drugs?

Answer 32

Statin drugs are HMG CoA reductase inhibitors. Since this enzyme is the rate limiting enzyme of cholesterol formation, inhibiting it will prevent the synthesis of cholesterol.