Cholesterol and Complex Lipids

Question 1

Major sources of liver cholesterol

Answer 1

1. Dietary cholesterol: 300-600 mg
2. Cholesterol synthesized in extrahepatic tissues
3. De novo synthesis in the liver: 1000 mg (recycled via LDL receptor)

Question 2

Major routes by which cholesterol leaves the liver

Answer 2

1. Free cholesterol secreted in the bile
2. Conversion to bile acids/salts
3. Secretion of VLDL

Question 3

Why is cholesterol important?

Answer 3

1. It is in cell membranes
2. Makes hormones like estrogen, testosterone, cortisol (steroid hormones)
3. Turns into bile for digestive processes

Question 4

Synthesis of cholesterol (start, end, key steps)

Answer 4

Happens in the fed state

1. Start at Acetyl-CoA –> Acetoacetyl CoA
2. Acetoacetyl CoA -(HMG CoA synthase)-> HMG CoA
   This is the same as ketone synthesis (occurs in mitochondria and fasting), and this happens in the cytosol at a fed state
3. HMG CoA –(HMG CoA reductase***)–> Mevalonic acid
   Key step, requires energy from NADPH for FA and cholesterol synthesis
4. Mevalonate–>isopentyl pyrophosphate–>geranyl pyrophosphate–>farnesyl pyrophosphate–>squalene–>lanosterol—>cholesterol
   Uses more ATP; remember geranyl and farnesyl

Question 5

Regulation of HMG CoA Reductase

Answer 5

• Regulation of gene expression by SREBP (Transcription)
• Degradation
• Phosphorylation of enzyme by AMP activated protein kinase: high AMP inactivates enzyme
• Hormonal regulation by insulin/glucagon (also affect transcriptional control)

Question 6

How to make phospholipids

Answer 6

1. Phosphatidic acid + activated headgroup, but how do you get the head group on there?
2. Use CDP to activate choline and then take a diacylglycerol and add CDP-Choline
3. Alternatively, activate the diacylclycerol with CDP and then add glycerol or inositol to the CDP-diacylglycerol

You can also switch out headgroups.

Question 7

PL headgroup names

Answer 7

1. Serine
2. Ethanolamine
3. Choline

Question 8

PL properties

Answer 8

1. Structural in the membrane

2. Signaling molecules as well

Question 9

Making sphingomyelin

Answer 9

1. Start with palmitoyl CoA, FA is built in –> Sphinganine
2. Sphinganine –(Fatty acyl COA) –> Ceramide
3. Ceramide – (Phosphatidylcholine)–> Sphingomyelin

PO4 and choline = polar headgroup

Question 10

3 main categories of lipids

Answer 10

1. Triacylglycerols (neutral)
2. Glycolipids
3. Phospholipids

Question 11

What kind of backbone for Galactocerebroside 3-sulfate

Answer 11

Ceramide

Question 12

Lipoprotein

Answer 12

Lipid + protein

Question 13

Chylomicron

Answer 13

Biggest particle, mostly TG

• Apo B 48
• Apo C2
• Apo E

Question 14

VLDL

Answer 14

5: 1 TG:CE
- Apo B100
- Apo C2
- Apo E

Question 15

Intermediate density lipoprotein (IDL)

Answer 15

50%:50%

• Apo B48 orApo 100
• C2
• E

Question 16

LDL

Answer 16

Mostly CE

• B100
• E

Question 17

HDL

Answer 17

Mostly CE, very little TG if at all

-Apo A1

Question 18

Order from biggest to smallest lipoproteins

Answer 18

Chylomicron>VLDL>IDL>LDL>HDL

Question 19

Apolipoprotein

Answer 19

1. Amphipathic - mix of areas that like water and that like lipid.
2. Long chain of amino acids

Question 20

Lipoprotein lipase

Answer 20

Takes TG and breaks off the FA to move them into the cell. Encounters in the capillary endothelium. This causes the chylomicron to continue to shrink –> IDL as the FA go into tissues. There is a cofactor needed for lipoprotein lipase (you need C2, else you cant break it down and you will have super high TG levels)

IDLs recycle to the liver with a receptor (Apo E - remnant receptor)

Question 21

Roles of chylomicron Apo proteins

Answer 21

Apo B48- keeps structure together
Apo C2 - for lipoprotein lipase
Apo E - allows to be cleared through the liver

Question 22

VLDL pathway

Answer 22

Body needs fat and the liver is the source of it.
1. Liver is the start, takes up FA and glycerol. Could burn them for energy for gluconeogenesis. Else, make TG in liver.
2. Comes out of liver as VLDL. (5:1 TG:CE)
Note: B48 and B100 are same gene product; B48 is 48% of gene product and B100 is 100% of product
3. Delivers liver fat to the tissues (circulates in bloodstream); encounters adipose tissue and muscles (like chylomicrons)
4. With C2 cofactor, lipoprotein lipase breaks down VLDL –> LDL
5. LDL recycled back to liver via LDL receptor - recognizes the B100 apoprotein. Worried about this because it can lead to atherosclerosis.

High input to liver can lead to high VLDL production, and eventual accumulation of LDL. These things can be diabetes etc.

Question 23

What happens if you lack LDL receptors?

Answer 23

Deficient LDL receptors = familial hypercholesterolemia; can have heart attack at 9 or 10 years old. Heterozygotes have half as many and have heart attacks at 20 yrs old

Question 24

HDL pathway

Answer 24

Helps keep the whole series of lipid pathways stable - trash truck; picks up lipids and apolipoproteins and delivers them elsewhere.

1. Start with liver and GI tract. Make Apo A1 - goes into the serum and circulates
2. Accumulates cholesterol via adenosine binding cassette A1 (ABC-A1). If you don’t get this, you have Tangier’s disease (orange tonsils,

Question 25

Major sources of cholesterol in diet

Answer 25

1. Eggs

2. Red meat

Question 26

Total cholesterol

Answer 26

Total cholesterol = VLDL + HDL + LDL
which also = HDL + TG/5 (from the ratio for VLDL) + LDL

Can count particles based upon Apo B

Question 27

3 functions of Apolipoproteins

Answer 27

1. Structural
2. Cofactors for LPL
3. Ligands for receptors