Cholesterol Metabolism (Exam 2, Lipid Lecture 2)

Question 1

Where is VLDL synthesized?

Answer 1

In the liver and is secreted as nascent with apo B-100

Question 2

What does VLDL contain?

Answer 2

Endogenous TAG

It does NOT carry dietary lipids

Question 3

How does VLDL become mature?

Answer 3

In blood, HDL will transfer apo C-II and apo-E, so now VLDL can interact with peripheral tissues

Question 4

What protein is required for LPL activation?

Answer 4

Apo C-II

Question 5

What happens once TAG is transferred to the peripheral tissues?

Answer 5

In the blood, some of the remaining TAG molecules are going to be transferred from VLDL to HDL. HDL will then head back to the liver.

Some of the cholesterol esters from HDL are then going to be transferred over to VLDL. This is accomplished by an enzyme called CETP.

Question 6

How are cholesterol esters from HDL going to be transferred over to VLDL?

Answer 6

Via CEPT enzyme

Question 7

What happens once the TAG molecules have been transferred from VLDL to HDL?

Answer 7

The apo C-II and apo-E proteins are also returned to HDL

Apo B-100 remains on VLDL

This equates to the brief phase of IDL (intermediate-density lipoprotein)

Question 8

IDL

Answer 8

Intermediate-density lipoprotein

Once the TAG, apo C-II and apo-E proteins are all returned to HDL

The liver can take up IDL via apo-E protein; however, most of the VLDL that is in circulation at this point is going to be used to form LDL. Remember LDL has a high concentration of cholesterol, not a whole lot of TAG molecules remain at this point.

Question 9

LDL

Answer 9

Low density lipoprotein

Contains: high concentration of cholesterol

Function: Delivery cholesterol to peripheral tissues, OR return it to the liver

70% of the cholesterol in the plasma is found in LDL

Question 10

What is the fate of cholesterol once it is inside the cell?

Answer 10

Within the lysosome, ACYL COA:CHOLESTEROL ACYL TRANSFERASE (ACAT) transfers FAs to cholesterol to form cholesterol esters for storage and potentially 3 other functions

Question 11

What are cholesterol esters used for within the lysosome?

Answer 11

1. Within the cell membrane phospholipid bilayer
2. Major precursor for synthesis of steroid hormones
3. Major precursor for the synthesis of bile acids

or storage, as well

Question 12

If cholesterol esters are being stored within the lysosome, what 3 important mechanisms occur?**

Answer 12

1. Inhibition of expression of HMG CoA reductase resulting in reduced synthesis of cholesterol
2. Degradation of HMG CoA reductase
3. Reduced expression and synthesis of LDL receptor

Question 13

(TRUE/FALSE)

The cell can make cholesterol itself.

Answer 13

TRUE

Question 14

What is a clathrin-coated vesicle?

Answer 14

When the LDL particle is endocytosed and brought into the cell.

Question 15

Where is HDL cholesterol formed?

Answer 15

The mature form will form in the blood

Lipid + apo A-1 secreted from the liver and intestines

HDL is poorly understood

Question 16

What is the function of HDL?

Answer 16

Serves as a circulating reservoir for Apo C-II and Apo-E, which it transfers over to the chylomicron and VLDL

Nascent HDL functions to uptake cholesterol from peripheral tissues and transport it to liver = “good cholesterol reputation.”

Question 17

LCAT

Answer 17

Lecithen:choleterol acyltransferase (LCAT)

Synthesized and secreted by the liver, binds to HDL and facilitates the uptake of cholesterol in the blood from peripheral tissues.

Aka- helps HDL take up peripheral cholesterol

Question 18

CETP

Answer 18

Cholester ester transfer protein (CETP)

Facilitates the transfer of cholesterol from HDL to VLDL during HDL metabolism.

This allows HDL2 to scavenge up more cholesterol from peripheral tissues on its way to the liver.

Question 19

What happens when HDL returns to the liver?

Answer 19

HDL returns to the liver and cholesterol is used for bile acid synthesis

Question 20

HMG CoA reductase

Answer 20

the rate limiting step in cholesterol synthesis within the cytoplasm

Question 21

Where can cholesterol be synthesized?

Answer 21

In most tissues:

Liver
Intestines
Adrenal cortex
Reproductive tissues

Question 22

Where do the carbons for cholesterol synthesis come from?

Answer 22

Acetyl-CoA

Cholesterol is made from acetyl-CoA fragments

Question 23

What is the initial step in cholesterol synthesis?

Answer 23

2 acetyl-CoA molecules come together to form ACETOACETYL-COA via THIOLASE (cytoplasmic).

Question 24

What is the main reducing agent in cholesterol synthesis?

Answer 24

NADPH

Question 25

What is the second step in cholesterol synthesis?

Answer 25

ACETOACETYL-COA combines with another acetyl-CoA to form HMG-CoA via HMG CoA synthase.

Question 26

What is the third step in cholesterol synthesis?

Answer 26

HMG-CoA will be reduced via HMG-CoA reductase w/ 2 NADPHs, forming MEVALONATE

Question 27

How is HMG-CoA reductase regulated?

Answer 27

1. Gene expression
2. Degradation
3. Covalent modulation

Question 28

Explain gene expression regulation of HMG-CoA reductase.

Answer 28

++ Insulin (increases the production of the enzyme)
— Glucagon (decreases production)

Question 29

Explain degradation regulation of HMG-CoA reductase.

Answer 29

High cholesterol will cause HMG-CoA reductase to bind proteins and tag itself for degradation by proteasome

Storage of cholesterol can signal to degrade the enzyme because the cell does not need to make any more cholesterol, if it is being taken into the liver.

Question 30

Explain covalent modulation regulation of HMG-CoA reductase.

Answer 30

ACTIVE = UNPHOS via PROTEIN PHOSPHATASE

INACTIVE = PHOSHORYLATED via AMPK (activated by AMP aka low energy in the cell)

Question 31

Which enzyme is targeted in statin medications?

Answer 31

HMG-CoA reductase enzyme as the statin works to inhibit this enzyme and prevents the body from making cholesterol.

Question 32

How is LDL formed?

Answer 32

VLDL –> IDL –> LDL