Exam 2: cholesterol

Cholesteryl esters in lipid droplets with TAGs.

Takes place in almost all tissues, but especially liver, intestine, adrenal cortex, and reproductive tissues. 

Cytosol 

Sources: Dietary, de novo synthesis, extrahepatic (HDL)

Excreted: VLDL, unmodified in bile OR converted to bile salts --> lumen and excreted via feces

• 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)

• 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

• 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.

• 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

ABCG5/8 is a cholesterol transporter found on boths ides going into lumen

Transporter for cholesterol into enteorcytes: NPC1L1

• 1. ABCG5/8; NPC1L1 (same with dietary cholesterol)
• 2. ABCB4
• 3. ABCB11; Bile Acid Transporter.

TAGs, CEs, PLs, ApoB48, free cholesterol, and fat soluble vitamins

Spherical aggregates of specific proteins - not molecules. 

• 1. Facilitate lipid transport in blood
• 2. Target lipoprotein components to specific tissues

Structural, enzyme activators, receptor site binders and blockers

Outside: apolioproteins, phospholipids, free cholesterol

Inside: TAGs, CEs.

• 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.

• 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

• 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

ApoE

• 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. 

• 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. 

• 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.

• 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. 

• 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). 

• 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.

• 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. 

CETP - cholesterol ester transfer protein transfers TAGs to HDL and CEs to VLDL.