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What is storage form of cholesterol and where are they found? Where does cholesterol synthesis take place in terms of tissues? cell area?
Cholesteryl esters in lipid droplets with TAGs.
Takes place in almost all tissues, but especially liver, intestine, adrenal cortex, and reproductive tissues.
What are sources of cholesterol? 3 How can cholesterol be excreted? 3
Sources: Dietary, de novo synthesis, extrahepatic (HDL)
Excreted: VLDL, unmodified in bile OR converted to bile salts --> lumen and excreted via feces
What can cholesterol turn into? 6
- 1. Steroid hormones
- 2. Vitamin D
- 3. BIle acids/salts
- 4. Lipoproteins
- 5. Sonic hedgehog - critical for morphogenesis and embryonic development
- 6. Cholesteryl esters (via ACAT and LCAT)
What is the rate-limiting enzyme for cholesterol synthesis? How is it regulated (5)
- 1. SREBP2 controls gene expression of HMG CoA reductase
- 2. 3. Insulin and Glucagon (via phosphatase and AMPK) - can be considered separate.
- 4. Cholesterol feedback inhibits HMG CoA synthase AND reductase
- 5. Statins inhibit HMG CoA reductase
How does the gut and how do macrophages interact with cholesterol?
- Gut: absorbs cholesterol from diet and bile
- Macrophages: Take up cholesterol from lipoproteins in blood, esterify cholesterol to form CEs, store CEs in lipid droplets, synthesize cholesterol.
How does liver interact with cholesterol? 6
- 1. Takes up cholesterol from diet/peripheral tissues
- 2. Esterifies cholesterol --> CEs
- 3. Stores CEs in lipid droplet with TAG
- 4. Secretes cholesterol and CEs in VLDL
- 5. Synthesizes de novo cholesterol
- 6. Synthesizes bile acids from cholesterol and secretes both cholesterol and bile acids into gall bladder
This is the slide with the transporters. Name the 3 ABC transporters and what they do. What does NPC1L1 do? What inhibits NPC1L1?
Which transporter is found both on enterocyte and hepatocyte? What is the transporter for de novo/dietary cholesterol into enterocyte?
ABCG5/8 is a cholesterol transporter found on boths ides going into lumen
Transporter for cholesterol into enteorcytes: NPC1L1
How do the following leave the hepatocyte and enter enterocyte?
3. Bile acids
- 1. ABCG5/8; NPC1L1 (same with dietary cholesterol)
- 2. ABCB4
- 3. ABCB11; Bile Acid Transporter.
What goes into a chylomicron? 6
TAGs, CEs, PLs, ApoB48, free cholesterol, and fat soluble vitamins
Give definition of lipoproteins. Are they molecules?
Spherical aggregates of specific proteins - not molecules.
What are functions of lipoproteins? (2)
What are 3 functions of apolipoproteisns?
- 1. Facilitate lipid transport in blood
- 2. Target lipoprotein components to specific tissues
Structural, enzyme activators, receptor site binders and blockers
What would be on the outside of a lipoprotein? (3) Inside? (2)
Outside: apolioproteins, phospholipids, free cholesterol
Inside: TAGs, CEs.
Who has the highest cholesterol percentage? Highest protein? Highest TAG?
- 1. Highest cholesterol - LDL, HDL, VLDL, Chylomicrons
- 2. Highest protein: HDL, LDL, VLDL, chylomicrons
- 3. Highest TAG: Chylomicrons, VLDL, LDL, HDL.
- TAG and protein are opposite
- Cholesterol is in direction of protein, but LDL wins.
Where is apoB100 found? (3)
- ApoB100 - VLDL, IDL, LDL
- ApoE - chylo, VLDL, IDL, HDL, remnants
- ApoCII - chylos, VLDL, IDL, HDL
- ApoB48 - chylos and chylo remannts
- ApoA1 - HDL, chylomicrons.
B100 - structural protein for VLDL and ligand for LDL receptorB48 - structural protein for chylomicrons, lacks LDL-R binding domain so can't bind to LDL-RCII - activates LPL (activated by insulin) to distribute FAs from TAGsA1 - Activates LCAT and is a structural protein of HDL
What are the functions of ApoB100, B48, CII, A1, E?
- B100 - structural protein for VLDL and ligand for LDL receptor
- B48 - structural protein for chylomicrons, lacks LDL-R binding domain so can't bind to LDL-R
- CII - activates LPL (activated by insulin) to distribute FAs from TAGs
- A1 - Activates LCAT and is a structural protein of HDL
What apolipoprotein do chylomicrons depend on for ligand binding?
Describe chylomicron metabolism 5 steps
- 1. Synthesis of chylomicron and secretion
- 2. Apo C and E are transferred to chylomicron from HDL
- 3. EC LPL activated by apoCII degrades TAG in CM
- 4. ApoCII is returned to HDL
- 5. CE rich CM remnants bind to ApoE to specific LDL-receptors for endocytosis in liver.
Describe VLDL metabolism (5 steps)
- 1. Liver secretes TAG-rich VLDL particlds
- 2. VLDL wanders around blood, collects ApoCII and ApoE from HDL (like CMs)
- 3. EC LPL activated by apoCII degrades TAG into FAs for uptake (apoCII activated by insulin)
- 4. VLDL gives HDL TAGS in exchange for CEs (using CETP) and returns ApoCII and ApoE
- 5) VLDL --> IDL --> LDL.
Describe LDL metabolism 5
- 1. Binding: LDL binds to LDL-R that recognize apoB100 - coated pit
- 2. Endocytosis: LDL-R complex is internalized via endocytosis of cell or by macrophages via scavenger R-s (NOTE: scavenger-Rs can't regulate how much LDL they take up)
- 3. Receptor recycling (endosome):
- 4. Lysosomal degradation (lysosome breaks into cholesterol and amino acids)
- 5. Functions of Cholesterol: is made into other things: membranes, vitamin D, steroid hormones, bile acids, lipoproteins, etc.
What happened in the Goldstein experiment? 4 things
- 1. Took skin cells from normal person and person with familial hypercholesterolemia.
- 2. Added media that did/did not contain serum cholesterol (LDL)/media with just free cholesterol.
- 3. Measured cell's ability to incorporate 14C acetate into cholesterol (remember cholesterol synthesis begins with acetyl CoA)
- 4. In familial hypercholesterolemia, LDL-R couldn't recognize LDL particle, so HMG CoA reductase kept synthesizing more cholesterol from acetate.
How does serum LDL cholesterol levels affect endogenous cholesterol synthesis? Go step by step
1. High serum LDL
2. Low serum LDL
- High serum LDL:
- 1. More cholesterol uptake into cell
- 2. Turns off transcription for HMG CoA reductase (chol synthesis), LDL-R, and by increasing ACAT (esterifies free cholesterol into esterified cholesterol for storage in cell).
- Low serum LDL:
- 1. Less cholesterol in cell
- 2. Active SREBP
- 3. Increases synthesis of cholesterol and LDL-R
- 4. Increased LDL-R brings more cholesterol into cell and lowers serum cholesterol! (increased HMG CoA reductase, LDL-R and decreased ACAT).
Where is HDL from? (2) Why is HDL considered a reservoir for? Function? How do ABC transporters help HDL?
- HDL is from liver and intestine, it is a reservoir for lipoproteins (particularly apoE and apoCII).
- function: To collect cholesterol from circulation and extrahepatic tissues to bring back to liver.
ABC transporters help HDL remove free cholesterol from plasma membranes of peripheral tissues.
Who does HDL trade apoE and apoCII with? 3
What does LCAT do and how does this differ from ACAT?Why is HDL so good for picking up cholesterol?
- chylomicrons, VLDL/IDL
- LCAT immediately esterifies free cholesterol transferred to HDL. ACAT is within a cell while LCAT is on HDL.
- HDL is good bc it has a ton of phospholipids which are great for emulsifying cholesterol for transport.
What does CETP do? Between who?
CETP - cholesterol ester transfer protein transfers TAGs to HDL and CEs to VLDL.