Lecture 45 Flashcards
What are lipoprotein particles?
1) spherical particles with varying amounts of lipid and protein
2) maintain solubility of constituent lipids
3) transport of lipids in plasma
What are major classes of lipoprotein particles?
1) chylomicrons
2) VLDLs - very low density lipoproteins
3) LDLs - low density lipoproteins
4) HDLs - high density lipoproteins
What are the principal lipid components of lipoproteins?
1) triacylglycerols
2) cholesterol esters
3) phospholipids
What are the principal protein components of lipoprotein particles?
1) apolipoproteins - five classes (A through E)
2) important in release of lipoprotein particles from cell
3) activate lipid processing enzymes in blood
4) mediate uptake of lipoprotein particles into cells
What is the principal component of a chylomicron?
90% triacylglycerols
Rank from smallest to largest the lipoproteins
1) HDLs
2) LDLs
3) IDLs
4) VLDLs
5) chylomicrons
Where is cholesterol absorbed?
Cholesterol is absorbed in the small intestine
and assembled into chylomicrons
What are 5 examples of clinical manifestations in hyperlipidemia?
Some clinical manifestations of hyperlipidemia:
1) Cutaneous xanthomas linked to elevated plasma chylomicrons and/or LDL.
2) Lipemic plasma (left), normal plasma (right).
3) Lipemia retinalis, elevated plasma triglyceride.
4) Tuberous xanthomas, usually on extensor surfaces.
5) Palmar crease xanthomas.
Where does chylomicron metabolism start and describe the process
Chylomicron metabolism starts in the intestine.
1) Chylomicrons are assembled in the intestine and contain apo B48
2) Chylomicrons are released into lymph
3) Chylomicrons acquire apo C-II and apo E from HDL in plasma
4) Apo CII on chylomicrons (or VLDLs) binds to lipoprotein lipase on the surface of non-hepatic tissues, hydrolyzes triglycerides
5) Chylomicron remnants depleted of glycerol and FFA transfer apo C-II to HDL
6) Remnants w/apoE and apoB48, bind to the apo E receptor on liver cells, resulting in the uptake of remnants
How is apoB pre-mRNA edited?
It is spliced from apoB-100 to apoB-48
Common variants of apolipoprotein E is a risk factor for what?
95% of late onset alzheimer’s disease
Summary of chylomicron interactions with HDL
1a) nascent chylomicrons assembled in intestine released into plasma w/ apoB-48, which is unique to nascent form
1b) HDL assembled in liver and intestine transfers apo CII/E to nascent chylomicrons
2) mature chylomicrons apo E and C-II added from HDL apoC-II activates lipoprotein lipase
3) lipoprotein lipase capillary walls, hydrolyzes TG delivers FFA into adipose & muscle
4) chylomicron remnants lack apoC-II, which is transferred to HDL
5) mature HDLs re-acquire apo C-II, also acquires cholesterol from membranes, accumulates apoCII/ and E, transferring them to VLDL & LDL, functions in reverse transport of cholesterol to liver
VLDL & LDL metabolism in the liver:
1) assembly and export of nascent VLDL containing apoB100
2) nascent VLDL acquires apoC-II and apoE from HDL
3) Lipoprotein lipase hydrolyzes TGs, FFA are taken up, LDL circulates
4) cholesterol is excreted as bile
5) LDL binds receptor on cells
6) LDL is taken up by cells, increasing intracellular cholesterol
Summary of VLDL & LDL interactions with HDL
1a) HDLs assembled in liver transfer apoCII/E to VLDLs
1b) nascent VLDLs assembled in liver mediated by apoB100
2) mature VLDLs apoE and CII are acquired from HDL apoCII activates lipoprotein lipase
3) lipoprotein lipase hydrolyzes TG FFA are delivered to adipose tissue & muscle
4) mature HDLs re -acquire apoCII/E from VLDLs
5) LDLs are derived from from VLDLs that no longer contain apoCII and E
What are general characteristics of HDL?
Synthesized in the liver and intestine secreted directly into the blood from liver and intestine protein rich express apo-AI and AII, apo-CII and apo-E nearly devoid of cholesterol and cholesterol esters
How is HDL exchanged with another apolipoprotein (HDL-apolipoprotein exchange)?
1) HDL transfers apo-CII and apo-E to chylomicrons
2) Chylomicrons return apo-CII to mature HDLs
3) HDL transfers apo-CII and apo-E to VLDLs
4) VLDL returns apo-CII and apo-E to HDLs
How is HDL exchanged with HDL and cholesterol/cholesterol ester exchange?
1) HDL can acquire cholesterol from chylomicrons, VLDLs or membrane and convert them to cholesterol esters
2) Cholesterol esters in HDL can be transferred to VLDLs and LDLs by cholesterol ester transfer protein (CETP - search for CETP inhibitors people with CETP deficiency have increased HDL lower risk of heart disease)
How is HDL exchanged in reverse cholesterol transport?
HDLs that are rich in cholesterol esters are returned to liver
What is torcetrapib?
1) Drug deveoped by Pfizer to treat high cholesterol
2) Inhibits cholesteryl ester transfer protein (CETP)
3) Blocks transfer of CEs from HDL to LDL
4) Increases HDL cholesterol
5) Decreases LDL cholesterol
Clinical trial terminated due to 60% increase in death in patients taking torcetrapib as compared to
What is the cholesterol paradigm of atherosclerosis?
FH is caused by defects in the regulation of cholesterol synthesis
What is Familial Hypercholesterolemia (FH)?
1) Caused by mutations in the gene encoding the LDL receptor (also known as the apoB-100/apoE receptor)
2) LDL receptor mediates cellular uptake of cholesterol by “receptor-mediated endocytosis”
3) When the LDL receptor functions normally increased blood cholesterol leads to increased LDL uptake into cells, resulting in increased cholesterol in cells and inhibition of cholesterol synthesis
4) When intracellular cholesterol is high, expression of cholesterol synthesis genes is blocked HMG CoA reductase is degraded
5) Extracellular region of LDL receptor mediates LDL binding
6) When LDL is bound, intracellular region signals receptor-mediated endocytosis
What are 4 classes of mutations in the LDL receptor in FH?
1) No receptors synthesized - accounts for approximately 50% of FH mutations
2) Receptors are made but retained intracellularly in the ER or golgi
3) Receptors reach cell surface, but lack normal LDL binding
4) Receptors reach cell surface and bind LDL, but are not clustered into coated pits and endocytosed
All of the above mutations lead to high blood cholesterol levels
Receptor-mediated endocytosis of LDL steps
1) Endocytosis of LDL bound receptor into cell
2) LDL dissociates from receptor in endosome
3) LDL receptors recycle to plasma membrane
4) ACAT acyl CoA cholesterol acetyltransferase converts cholesterol to a cholesterol ester for storage
What does an oversupply of cholesterol do to ACAT?
It down regulates cholesterol synthesis genes by giving positive feedback to ACAT, producing more cholesterol esters, and storing them.
What is PCKS9?
1) a new drug target for reducing LDL levels
2) PCKS9 is a normal human protein that binds the LDL receptor and promotes LDLR degradation in lysosomes
