Lipoproteins (20)

What is orlistat?

Drug that works as a lipase inhibitor

What is olestra?

An artificial fat that is used as an additive bc it cannot be hydrolyzed by lipases = excreted

General structure of a lipoprotein

1. Polar surface

2. Neutral lipid core

Components of the polar surface (3)

1. Apolipoprotein

2. Free cholesterol

3. Phospholipids

Components of the neutral lipid core (2)

1. Cholesteryl ester

2. Triglycerides

Lipoproteins are overall…

Amphiphilic

Give the general definition of a lipoprotein

Lipid carriers composed of a neutral lipid core, a monolayer of polar surface lipids and at least one apolipoprotein

Name lipoproteins from lowest to highest density (6)

1. Chylomicrons

2. Chylmomicron remnant

3. VLDL

4. IDL

5. LDL

6. HDL

What are apolipoproteins?

Amphipatic proteins that serve as ligand for lipoprotein recognition and docking

Steps of exogenous lipoprotein metabolism (4)

Chylomicron → LPL hydrolyzes the TGs in its core → Chylomicron remnants → Liver

What are the inhibitors and activators of LPL in exogenous lipoproteins?

ApoC3 (-)

ApoC2 (+)

Discuss the apolipoproteins of chylomicrons

ApoC's + ApoE + ApoB-48

What happens to those apolipoproteins once a chylomicron remnant is formed?

No more ApoC’s

Discuss the lifespan of chylomicron remnants

1-2h : so not present if not eating!

How are the chylomicrons remnants taken up by the liver?

By LDLR (affinity for apoE) and LRP (affinity for apoB-48)

Steps of endogenous lipoprotein metabolism (5)

Liver → VLDL → LPL hydrolyzes TGs → IDL → Hepatic Lipase → Liver OR LDL

Discuss the apolipoproteins on VLDLs

ApoC’s + ApoE + ApoB-100

Discuss VLDL’s lifespan

It is continuously produced, regardless of meal presence

What’s the difference between ApoB-100 and ApoB-48?

They’re from the same gene but ApoB-48 was produced from exon skipping (48% of the protein length)

What is HL’s role?

To get rid of as many TG’s as possible

What is the remaining apolipoprotein on LDL?

ApoB-100

What is LDL’s role?

It has a high content of cholesterol esters = excellent vehicle for cholesterol to peripheral tissues

What is classified as a peripheral tissue?

Everything but the liver

Why is cholesterol needed?

1. Fluidity of plasma membrane

2. Membrane synthesis

3. Hormone synthesis

4. Regulation of gene transcription

Describe the mechanism of cholesterol uptake (5)

1. LDL receptor on clathrin-coated pit binds the ApoB protein

2. Endosome formation

3. Secondary lysosome formation as the endosome merges w/ a lysosome

4. Hydrolysation of cholesterol esters into cholesterol

5. Cholesterol is taken up in the ER through endocytosis

Simplified steps of HDL metabolism

Tissue → HDL → Liver

What is the role of HDL?

Reverse Cholesterol Transport

What apolipoproteins are on HDL’s surface?

ApoA-1

Step #1 of HDL metabolism

High cholesterol induces ABCA1 transcription = flopping of cholesterol from inner to outer MM = interaction with ApoA-1

What is formed after step #1?

Nascent or Pre HDL

Step #2 of HDL metabolism

Formation of discoidal HDL from the helices = dissociates from ABCA1

Step #3 of HDL metabolism

LCAT esterification of cholesterol = spherical HDL formed bc cholesterol esters don’t want to interact w/ the hydrophilic environment

Step #4 of HDL metabolism

CETP exchanges CE and TGs between HDL₃ and VLDL

Discuss the shape and interactions of CETP

Tube + totally hydrophobic

Step #5 of HDL metabolism

HDL₂ docks to SRB1 to be taken up by the liver and empties CE and TGs

Step #6 of HDL metabolism

Undocking of lipid-poor ApoA-1

How are the CEs taken up by the liver used?

Recycled for bile salt biosynthesis (Cholesterol + Glycine/Taurine)

What are the 2 scenarios that lead to high CVD risk?

1. LDLR deficiency: bc too much LDL

2. ABCA1 deficiency: too little HDL