Cholesterol and Complex Lipids Flashcards
Major sources of liver cholesterol
- Dietary cholesterol: 300-600 mg
- Cholesterol synthesized in extrahepatic tissues
- De novo synthesis in the liver: 1000 mg (recycled via LDL receptor)
Major routes by which cholesterol leaves the liver
- Free cholesterol secreted in the bile
- Conversion to bile acids/salts
- Secretion of VLDL
Why is cholesterol important?
- It is in cell membranes
- Makes hormones like estrogen, testosterone, cortisol (steroid hormones)
- Turns into bile for digestive processes
Synthesis of cholesterol (start, end, key steps)
Happens in the fed state
- Start at Acetyl-CoA –> Acetoacetyl CoA
- 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 - HMG CoA –(HMG CoA reductase***)–> Mevalonic acid
Key step, requires energy from NADPH for FA and cholesterol synthesis - Mevalonate–>isopentyl pyrophosphate–>geranyl pyrophosphate–>farnesyl pyrophosphate–>squalene–>lanosterol—>cholesterol
Uses more ATP; remember geranyl and farnesyl
Regulation of HMG CoA Reductase
- 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)
How to make phospholipids
- Phosphatidic acid + activated headgroup, but how do you get the head group on there?
- Use CDP to activate choline and then take a diacylglycerol and add CDP-Choline
- Alternatively, activate the diacylclycerol with CDP and then add glycerol or inositol to the CDP-diacylglycerol
You can also switch out headgroups.
PL headgroup names
- Serine
- Ethanolamine
- Choline
PL properties
- Structural in the membrane
2. Signaling molecules as well
Making sphingomyelin
- Start with palmitoyl CoA, FA is built in –> Sphinganine
- Sphinganine –(Fatty acyl COA) –> Ceramide
- Ceramide – (Phosphatidylcholine)–> Sphingomyelin
PO4 and choline = polar headgroup
3 main categories of lipids
- Triacylglycerols (neutral)
- Glycolipids
- Phospholipids
What kind of backbone for Galactocerebroside 3-sulfate
Ceramide
Lipoprotein
Lipid + protein
Chylomicron
Biggest particle, mostly TG
- Apo B 48
- Apo C2
- Apo E
VLDL
5: 1 TG:CE
- Apo B100
- Apo C2
- Apo E
Intermediate density lipoprotein (IDL)
50%:50%
- Apo B48 orApo 100
- C2
- E
LDL
Mostly CE
- B100
- E
HDL
Mostly CE, very little TG if at all
-Apo A1
Order from biggest to smallest lipoproteins
Chylomicron>VLDL>IDL>LDL>HDL
Apolipoprotein
- Amphipathic - mix of areas that like water and that like lipid.
- Long chain of amino acids
Lipoprotein lipase
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)
Roles of chylomicron Apo proteins
Apo B48- keeps structure together
Apo C2 - for lipoprotein lipase
Apo E - allows to be cleared through the liver
VLDL pathway
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.
What happens if you lack LDL receptors?
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
HDL pathway
Helps keep the whole series of lipid pathways stable - trash truck; picks up lipids and apolipoproteins and delivers them elsewhere.
- Start with liver and GI tract. Make Apo A1 - goes into the serum and circulates
- Accumulates cholesterol via adenosine binding cassette A1 (ABC-A1). If you don’t get this, you have Tangier’s disease (orange tonsils,
Major sources of cholesterol in diet
- Eggs
2. Red meat
Total cholesterol
Total cholesterol = VLDL + HDL + LDL
which also = HDL + TG/5 (from the ratio for VLDL) + LDL
Can count particles based upon Apo B
3 functions of Apolipoproteins
- Structural
- Cofactors for LPL
- Ligands for receptors