Lecture 2 Flashcards
Apo B-48
Unique to chylomicrons
Carries dietary TAG, cholesterol, fat soluble vitamins, and cholesterol esters to peripheral tissues.
Made in the intestinal mucosal cells
Truncated form of Apo B100
Chylomicron metabolism Steps
- ) Nascent Chylomicrons are released into the lympahtic circulation and then the blood.
- )Apo E and Apo C are added to the nascent chylomicron in the blood.
- )LPL on the capillary walls is activated by Apc C-II to hydrolyze TAG
- ) Paritcle decreased in size and increases in density
- ) Apo C is returned to the HDL creating a chylomicron remnant.
- ) Remnant is taking up by the liver through recognition of Apo E
Lipoprotein Lipase Structure
LPL is an antiparallel Homodimer
N terminal domain- Lypolytic site
C teminal domain- binds to the lipoprotein ( Apo C-11) and gives substrate specificity
Patients with deficiency of LPL or ApoC-II
accumulate cylomicron TAG in the plamsa and are at higher risk for panceatitis
VLDL
very low density lipoproteins
produced by the liver
contain Apo B-100
functions to ccarry lipids from the liver to pheripheral tissues.
VLDL Metabolism Steps
- )nascent VLDL is secreted into the bloodstream by the liver.
- )Apo E and Apo C are added from HDL . Some TAGs are exchanged for cholesterol esters from HDLs, in a reaction catalyzed by cholesterol ester exchange protein (CETP)
- )LPL on the capillary walls is activated by Apc C-II to hydrolyze TAG
- ) VLDL is converted to LDL in the blood stream, adn Apo C and APo E are returned to HDLs
- ) LDL particle binds to a receptor on hepatocytes and extra hepatic tissue.
hepatic steatosis
(Nonalcoholic Fatty liver)
caused by an imbalance of TAG synthesis and VLDL secretion
familial Type III hyperlipoproteinemia
Apo E-2 binds poorly to receptors.
They also have hypercholesterolemia and premature athlerosclerosis.
Apo E4 significance
confers increased susceptibility and decreased age of onset of alzheimer’s disease.
CETP
Cholesterol ester transfer protein
Exchanges TAGs from VLDLs for Cholesterol esters from HDL.
Driven by increased concentration of TAGs
(explains why increased TAG in the blood results in increased cholesterol return to the liver via VLDLs and IDL particles)
ACAT
Acyl CoA cholesterol acyltransferase
Cholesterol to Cholesterol ester (form that can be stored in cells when cholesterol is not immediately needed)
LDL Metabolism Steps
1.) ApoB 100 binds
2.) complexed endocytosed in clathrin coated pits
3.) fusion with over vesicles forms endosomes
4.)pH of endosome drops through action of ATP dependant proton pump, in order to seperate the LDL from the LDL receptor
5.) A.) receptor is recycled to the membrane
B.) lysosomal hydrolases degrade LDL
LDL
functions to provide cholesterol to the peripheral tissues and return it to the liver.
contains less TAG than VLDL and more cholesterol and cholesterol esters
familial Type II hyperlipoproteinemia
deficiency in LDL receptor, or Apo B-100 (autosomal recessive)
(autosomal dominant form has increased activity of a protease that degrades the LDL receptor)
oversupply of cholesterol can diminish expression of
Liver LDL receptor and HGM CoA reductase (first step in cholesterol biosysthesis)
LDL receptor domains
1.) LDL binding region (decreased pH causes the Ca from this region to be released causing a conformation change in region 2)
2.) EGF-like and transducin beta subunit-like domain
(where conformational change occurs in response to acidic pH)
3.) N-linked oligosaccaride region
4.) O-linked oligosaccaride region (3&4 extent LDL binding region away from membrane surface)
5.) alpha-helical pass
6.) Cytosolic domain that associates with clathrin coated pits
Tangier Disease
Deficiency of ABCA1 (which catalyzes efflux of cholesterol from pheripheral tissues)
lead to absence of HDL particals because free ApoA-1 gets degraded
LCAT
lecithin cholesterol acyl transferase
activated by Apo A-1
esterifies choleserol taken up by HDLs (this maintains the cholesterol gradient so HDLs can continue taking up more cholesterol)
HDL
formed in blood by addition of lipids to ApoA-I (which is synthesized in the liver and intestines)
circulating supplier of Apo E and Apo C
Takes up cholesterol from peripheral tissues and return it to the liver as cholesterol esters
SR-B1
scavenger receptor
binds HDL and allows the liver to take up Cholesterol esters from the HDL
SR-A
Allows macrophages to endocytise LDLs that have undergone oxidative damage, when this happens macrophages turn into foam cells which participate in plaque formation.
Athleroslerotic plaques and thrombus formation
- ) A cap forms over the plaque obstruction the blood vessel
- ) vascular smooth muscle cells migrate from the tunica media and secrete plaque matrix material and metaloproeases that thin the fibrous cap.
- ) cap eventually ruptures exposing cap contents to procoagulants within the circulation.
