Cholesterol Synthesis And Membrane Lipids

Question 1

What is the function of cholesterol?

Answer 1

Regulated and stabilizes the correct fluidity of the plasma membrane which is especially important due to change in fatty acid fluidity at different temperatures

Question 2

Where does cholesterol. Synthesis Take Place?

Answer 2

Mainly in the liver, only the liver can use cholesterol for. Bile acid synthesis

Question 3

Why is cholesterol synthesis needed in the brain?

Answer 3

In the brain due to the blood-brain barrier

Question 4

Where is cholesterol used for de-novo steroid synthesis?

Answer 4

1. Adrenal cortex(cortisol, aldosterone, androgens)
2. Testes (testosterone)
3. Ovaries (estradiol)

Question 5

Insulin activates hepatic synthesis of ….

Answer 5

Fatty acid and of cholesterol

Question 6

What are the first 4 steps of cholesterol synthesis ?

Answer 6

1. Only cytosolic Acetyl CoA is used (18 times) and many molecules of NADPH are needed Acetyl CoA is formed by citrate lyase. NADPH is formed in the HMP and by hepatic malic enzyme
2. HMG CoA is synthesized using 3 Acetyl CoAs in cytosol
3. Mevalonate is formed in the regulated step catalyzed by HMG CoA reductase
4. Mevalonate-PP is decarboxylated to isopentenyl-PP(IPP): The 5”C” building block

Question 7

What are the last 5 steps of cholesterol synthesis?

Answer 7

5. The 5-carbon building block is used to form geranyl-PP(10C) and then farnesyl-PP(15C)
6. Two Farnese-PP are linked to each other to form squalene(30C)
7. The first sterol formed is lanosterol(30C)
8. After many steps cholesterol(27C) is formed
9. The synthesis of cholesterol uses many molecules of NADPH especially after formation of lanosterol

Question 8

What is the regulated enzyme of cholesterol synthesis?

Answer 8

HMG CoA reductase is the regulated enzyme.

Expression is inhibited by cholesterol

HMG CoA reductase forms mevalonate and uses 2 NADPH

Question 9

Where is the cell does cholesterol synthesis take place?

Answer 9

Takes place in cytosol and at SER( HMG CoA reductase)

Question 10

How is cholesterol synthesis regulated?

Answer 10

1. Substrate availability
2. Serum insulin/glucagon ratio
3. Cholesterol itself

Question 11

How can HMG CoA be activated without hormones?

Answer 11

Activation of HMG COA reductase by substrate availability (HMG CoA in cytosol)

Question 12

How is HMG CoA reductase inhibited without hormones?

Answer 12

• inhibition of HMG CoA red7ctase by phosphorylation by AMP-kinase at a state of low energy in the cell (high AMP)
• inhibition of HMG CoA reductase at high cytosolic cholesterol by inhibiting transcription of HMG CoA reductase and by activating early degradation of the present enzyme

Question 13

What is the role of insulin in HMG CoA reductase ?

Answer 13

Insulin favors usage of glucose for eventual cholesterol synthesis

Short term: insulin leads to the active dephosphorylation of. HMG COA reductase.

Long term: insulin induced HMG CoA reductase

Question 14

What is the function of glucagon of HMG COA reductase regulation?

Answer 14

• Glucagon signals low blood glucose levels
• Liver stops the synthesis of cholesterol and focuses on gluconeogenesis
• glucagon leads to the phosphorylated inhibited HMG CoA reductase. Glucagon uses the cAMP messenger system . Protein kinase A phosohorylates AMPK-kinases that will activate AMP-Kinase

Question 15

What are the other functions of intermediates of cholesterol synthesis?

Answer 15

1. Geranyl-groups are used to anchor proteins in the cell membrane
2. Farnesyl-groups are needed in specific proteins
3. Farnesyl-PP(FPP) branches out for the synthesis of:
   a. CoQ of the ETC (FPP and many IPPs are used
   b. Dolichol-PP needed for N-glycosylation of proteins

Question 16

What happens if there is a defect in the formation of ring B of cholesterol?

Answer 16

Leads to Microcephaly and early death

Question 17

Describe the plasma membrane

Answer 17

• contains free cholesterol in both layers
• Cholesterol and fatty acid composition determine the fluidity
• Glycolipids only found in the oute Layer

Question 18

Describe composition of membrane separating cell organelles

Answer 18

• no cholesterol
• Fatty acid composition determines fluidity
• Cardiolipin in inner mitochondrial membrane

Question 19

How does temperature affect cholesterol effect on plasma membrane fluidity?

Answer 19

Low temperatures: the fatty acyl groups are stiffer and cholesterol increases the membrane fluidity by separating them and preventing close packing

At high temperatures: the fatty acyl groups are more fluid and cholesterol decreases the membrane fluidity with its steroid ring system and slows down the movement of the esterified fatty acids

Question 20

What are the major components of membranes?

Answer 20

Phosphatidylethanolamine(PE)

and phosphatidylcholine(PC)

They are both uncharged

Question 21

What is the phospholipid composition of the outer leaflet of the phospholipid membrane?

Answer 21

The outer leaflet contains mainly phosphatidylcholine(PC), sphingomyelin (SM), and only some phosphatidylethanolamine(PE)

Question 22

What does the inner leaflet of the phospholipid bilayer membrane contain?

Answer 22

The inner leaflet contains mainly phosphatidylethanolamine (PE), some phosphatidylcholine (PC), phosphatidylserine(PS), phosphatidylinositol (PI)and PIP2

Question 23

Where can sphingomyelin be found?

Answer 23

The sphingophospholipid sohingomyelin can be found in in RBC as it is abundant there

It is also a major structural component/phospholipid in myelin of nerve fibers

Question 24

Describe the structure of sphingomyelin

Answer 24

It contains the polar head group phosphocholine bound to ceremide

Question 25

The inner leaflet contains phosphatidylserine . Give its structure and function

Answer 25

Phosphatidylserine(PS) is overall negatively charged and normally found in the inner leaflet of the plasma membrane.

It signals cell degradation when found in the outer leaflet

Question 26

Where are phosohatidylinositol (PIP) and PIP2 found? Give the structure of PI and its function

Answer 26

Phosphatidylinositol (PI) is negatively charged and contains arachadonic acid

In the inner leaflet of the plasma membrane, some PI is phosphorylated to PIP2 for the second messengers system

Question 27

Where can the phosoholipid cardiolipin be found?

Answer 27

In the inner mitochondrial membrane

Question 28

What is the structure of cardiolipin?

Answer 28

Cardiolipin contains 2 phosphatidic acids linked by glycerol(also named Diana-phosphatidylglycerol)

Cardiolipin contains four fatty acids, often linoleic acids

Question 29

Where can glycosphingolipids be found?

Answer 29

Glycosphingolipids are found only in the outer leaflet of the plasma membrane (brain and peripheral nervous tissue)

Question 30

Describe the 4 glycosphingolipids

Answer 30

1. Cerebrosides contain ceremide and one sugar
2. Globosides are formed from cerebrosides (more sugars)
3. Sulfatides- contain galactosyl residues
4. Gangliosides- are globosides after the addition of N-Acetyl- neuramanic acid (NANA or Salic acid ) they are primarily found in CNS