Blood Lipoproteins

Question 1

Lipoprotein structure

Answer 1

• Inner hydrophobic core: TAG and cholesterol esters

- Shell of amphipathic phospholipids, cholesterol, and apolipoproteins

Question 2

Functions of apolipoproteins

Answer 2

• Recognition sites for cell surface receptors
• Activators for enzymes in lipoprotein metabolism
• Transferred between lipoproteins

Question 3

Apo A-1

Answer 3

• Synthesized in liver and intestine
• Abundant in HDL
• LCAT activator (transfers a FA from lecithin to cholesterol to generate CE)
• RCT involvement (Transfer of cell cholesterol by ABCA1 to nascent HDL and delivery of C and CE on HDL to the liver)
• Antiatherogenic protein

Question 4

Apo A-2

Answer 4

• Synthesized in liver, present with A1 in some HDL
• Activated LDL and inhibits LCAT
• May be proatherogenic

Question 5

Apo B-100

Answer 5

Produced in liver, binds to lipids provided by MTP to assemble VLDL

• One copy of Apo B-100 for each VLDL particle
• Measurement of B-100 in plasma reflects particle number

Question 6

Apo B-48

Answer 6

• Produced in intestine (!)
• Truncated form of Apo B-100
• Involved in chylomicron metabolism
• Not recognized by LDL receptor

Question 7

APO C1, C2, C3

Answer 7

• ApoCs can be exchanged freely among LP particles
• Important for TG metabolism: either interfere with recognition of apoE by LP receptors or displace apoE from lipoproteins
• ApoC2 activates LPL and ApoC3 inhibits LPL

Question 8

Apo E

Answer 8

• Associated with all LPs except LDL
• Recognized by LPLR and LRP which mediates hepatic upstate of CM and VLDL and IDL remnants.
• Primarily responsible for intestinal clearance of LPs after a mean and clearance of VLDL and IDL before they are converted to LDL
• 3 isoforms
• Apo E3 is most common
• Apo E2 associated with greater risk for dysbetalipoproteinemia
• Apo E4 associated with Alzheimers

Question 9

Chylomicron metabolism

Answer 9

1. Apo B-48 formed from Apo-100 and then nascent chylomicron is transferred from ER to Golgi and packaged into secretory vesicles that fuse with the plasma membrane to enter the lymphatic system and blood
2. Nascent CM receives Apo E amd Apo C from HDL particles
3. LPL activated by apo C2, hydrolyzes TAG to yield FAs or glycerol
4. Particle decreases in size and increases in density. Apo-C including C2 are returned to HDL creating a chylomicron remnant
5. Chylomicron remnant taken up by the liver by ApoE binding to specific lipoprotein receptors followed by endocytosis, lysosomal enzymes degrading remnant components to cholesterol, AA, and FAs, and recycling of receptors

Question 10

Lipoprotein lipase

Answer 10

• Antiparallel homodimer
• N terminal domain: lipolytic site
• C terminal domain: binds to the LP particle and gives substrate specificity

Question 11

VLDL metabolism

Answer 11

1. VLDLs produced by the liver and secreted into the blood containing Apo B-100
2. Obtain Apo E and Apo C2 from HDL particles. Some TAGs transferred from VLDL to HDL in exchange for cholesterol esters in a reaction catalyzed by CETP
3. TAG degraded by LPL as described for chylomicrons
4. VLDL converted to LDL in the blood with IDL or VLDL remnants observed during the transition. Apo C2 and Apo E are returned to HDL particles.
5. LDL particle binds to a specific receptor on the surface of hepatocytes and extra-hepatic tissues

Question 12

Function of cholesterol ester transfer protein

Answer 12

• CETP
• Catalyzes exchange of TAG from VLDL with CE from HDL
• Greater TAG containing lipoprotein particles concentration in blood the greater the rate of exchanges

Question 13

Synthesis of Cholesterol Ester by ACAT

Answer 13

• Acyl CoA cholesterol acyltransferase (ACAT)
• Esterifies cholesterol if it is not needed immediately for a synthetic or structural purpose
• ACAT activity increases by the presence of an oversupply of intracellular cholesterol

Question 14

LDL particles

Answer 14

• Less TAG but more cholesterol and cholesterol esters than their VLDL predecessors
• Function to provide cholesterol to the peripheral tissues and return it to the liver
• Bind LDL receptors which recognize Apo B-100 and Apo E receptors

Question 15

Steps in uptake and degradation of LDL particles

Answer 15

1. LDL receptors are glycosylated transmembrane proteins which are clustered in clathrin coated pits
2. After binding, the LDL receptor complex is endoxytosed with the assistance of clathrin in forming the coated vesicle.
3. Coated vesicle loses its clathrin coat and fuses with other such vesicles to form endosomes
4. The pH of the endosome drops based on ATP dependent proton pumping into the endosome. Uncouples the receptor from the LDL particle. Separate into distinct areas of what is called the CURL
5. Receptors recycled to the plasma membrane and the endosome fuses with a lysosome. Lysosome hydrolases degrade the LDL (or CM or IDL) releasing AAs, FAs, cholesterol, and phosholipids,
   - Overexpression of cholesterol prevents LDL receptor expression

Question 16

LDL receptor

Answer 16

• Six regions
• Region 1: LDL binding domain
• Region 2: Epidermal growth factor like and transducin B subunit like domain forms a propeller like structure. Impacted by pH.
• Region 3: N-liked oligosaccharide domain
• Region 4: O-linked oligosaccharide domain
• Region 5: 22 AA alpha helix through membrane
• Region 6: Cytosolic domain that associates with clathrin coated pit and initiates endocytosis when LDL is bound

Question 17

Metabolism of HDL

Answer 17

• Circulating supplier of Apo C2 and Apo E
• Esterification of cholesterol: LCAT activated by Apo A-1 and transfers FA from C2 of PC cholesterol which produces hydrophobic CE and lysoPC. CETP exchanges CE from HDL to VLDL with concurrent exchange of TAG from VLDL to HDL
• Reverse cholesterol transport: Efflux of cholesterol is catalyzed by ABCA1. Uptake of cholesterol from liver involves SR-B1 that binds HDL on the surface of hepatocytes and selectively takes up CEs from the particle.