Ch. 18 Plasma Lipoproteins Flashcards
Describe the structure and composition of plasma lipoproteins
Outer vs. inner shell
Shape
Types
- Outer shell: amphipathic apolipoproteins, phospholipids, nonesterified cholesterol
- Hydrophobic core: Triglycerides & cholesterol esters
- Shape: spherical (except new HDLs-discoidal but become spherical by LCAT)
- Types:Chylomicrons, VLDL, LDL, HDL
What are are the 2 principal TG carriers?
Chylomicrons and VLDL
What are the 2 main cholesterol transporters?
LDL and HDL
Describe the relationship (synthesis) between Apo B-48 and Apo B-100.
Apo B-48 from intestine (contains deaminase). Apo B-48 deamination from C to U (introduce stop codon so only 48% of Apo B-100)
Apo B-100 from liver.
Apo B 48 unique to chylomicrons. Syn starts on RER, moves to golgi. Loaded onto chylomicron via triacylglycerol transfer protein.
Describe the relationship between Apo A-1 and HDL.
1:1 ratio, so can measure HDL concentration directly by measuring Apo A-1 in blood.
List the lipoprotein particles by size from smallest to largest
HDL, LDL, VLDL, Chylomicrons
List the lipoproteins in order by density from least to greatest
Chylomicron, VLDL, LDL, HDL
The more dense a lipoprotein, the ______ the level of lipid, and the _____ the level of protein
lower, higher
Ex. HDL has less lipids than a chylomicron, which has more lipid than protein
Metabolism of chylomicrons
Exogenous lipid transport
- Dietary lipids absorbed by intestinal cell
- Packaged into chylomicron (TG, cholesterol, cholesterol esters, and lipids) + Apo B-48)
- Enter lymphatic system as nascent chylomicron, then blood stream
- Receive apo E and C II from HDL
- Apo C-II activates lipoprotein lipase (LPL) located mostly in adipose, cardiac, and skeletal muscle tissue (not liver)
- Hydrolyze triacylglycerol to yield fatty aicds and glycerol
- Return Apo C-II to HDL
- Chylomicron remnant
- CE-rich remnant bind apo E to receptor in liver and endocytosed
What apoproteins are these associated with? Function?
A-I
B-100
B-48
C-II
D
E2-4
A-I: HDL Activates LCAT
B-100: VLDL/LDL: Necessary for triacylglycerol secretoin, binding to cell receptor
B-48: Chylomicron
C-II: Chylomicron, VLDL Activates LPL
D: HDL LCAT reaction, cholesterol ester transfer
E2-4: VLDL, IDL, HDL Binding to specific receptors
VLDL Metabolism
- Liver secretes TAG-rich nascent VLDL; B-100 attached
- Acquire apo C and E from HDL in blood
- VLDL
- C-II activates LPL and degrades TAGs
- IDL (VLDL remnant)
- Apo C-II and E returned to HDL
- LDL (source of cholesterol for body)
- Bind to LDL receptors of extrahepatic and liver tissues (LDL receptor mediated endocytosis)
How are the # of LDL receptors on membrane regulated?
Degree of accumulation of intracellular cholesterol. More intracellular cholesterol means downregulate the number of receptors (so you absorb less since you already have enough)
What are 5 possible pathways for the free cholesterol released into the liver?
- Incorporate into plasma membrane
- Inhibit new LDL receptor synthesis
- Inhibit cholesterol synthesis
- Microsomal ACAT (storage) activity stimulation
- Increased activity of 7-hydroxylase in bile acid synthesis
LDL receptor mediated endocytosis
Recognize Apo B-100 or E
- LDL receptors (-) charged glycoproteins clustered in clathrin pits (stabilizes shape of pit)
- LDL apo B100 or E binds to receptor
- Complete endocytosis
- Vesicle loses clathrin coat and fuses with other vesicles (form endosome)
- pH decreases (more acidic due to proton-pumping activiting of endosomal ATPase) allows separation of receptor from LDL - CURL Compartment for Uncoupling of Receptor and Ligand
- Receptors recycled back to membrane and lipoprotein remnants in vesicles travel to lysosome and degraded, releasing free cholesterol, amino acids, fatty, and phospholipids
HDL metabolism
Formed by
Function
Formed by Apo A-1 secreted by liver and intestines that combines with lipid. Discoidal nascent HDL contains mostly phospholipid PC turns into spherical mature HDL by acquiring free cholesterol from peripheral tissue.
Function: Reservoir of apolipoproteins, uptake of unesterified cholesterol, esterification of cholesterol
Esterification of cholesterol
When free cholesterol taken up by HDL, immediately esterified by PCAT (LCAT). Phosphatidylcholine/lecithin cholesterol acyltransferase in plasma and made by liver.
- PCAT binds to nascent HDL and activated by Apo A1
- PCAT transfers fatty acid from C2 of PC to cholesterol.
- Hydrophobic cholesteryl ester made and moves to core of HDL
- HDL3 (cholesteryl-ester poor) but acquires more cholesteryl esters and becomes…
- HDL2
- Carry cholesteryl esters back to liver
How are cholesteryl esters transferred to LDL and VLDL?
Cholesterol ester transfer protein (CETP) moves choesteryl esters from HDL to VLDL in exchange for TAGs and apo D.
Reverse cholesterol transport
- Efflux of cholesterol transport mediated by ABCA1 transport protein
- Esterification of cholesterol
- HDL transported to liver
- Uptake of cholesteryl esters by SR-B1 receptors
Diseases associated with ABCA1
- Tangier disease: absence of ABCA1 transporters
- CF Cystic fibrosis
- EOMD: Early onset macular degeneration
- SSL: Sitosterolemia
- ALD: Adrenoleukodystrophy
- Zellweger syndrome
- PFIC: Progressive familial intrahepatic choliestasis
What lipoproteins are in excess with the following hyperlipoproteinemia phenotypes I?
- Familial lipoprotein lipase deficiency: Hypertriacylglycerolemia due to deficiency of LPL, abnormal LPL or apo CII causing inactive LPL. Low levels of LDL and HDL. No increased risk for heart disease
What is the role of oxidized lipoproteins in plaque formatino on arterial wall?
- Endothelial injury by oxidized LDL
- Monocytes adhere to endothelial cells and enter intima to become macrophages
- Macrophages phagocytose excess oxidized lipoproteins via scavenger receptors
- Foam cells
- Accumulate and release growth factors/cytokines that stimulate migration of SMC from media to intima
- SMC proliferate and produce collagen, take up lipids, and become foam cells
7.
3 Potential mechanisms of antiatherogenic effects of HDL cholesterol
- Inhibit conversion from LDL to oxidized LDL
- Prevent monocyte adhesion to endothelium
- Prolong half-life of prostacyclin produced by endothelial cells to promote vasodilatory effects
Cholestyramine and colestipol
nonabsorbable resins that intterupt enterohepatic circulation of bile acids
Nicotinic Acid (Vitamin B3)
Reduce VLDL and LDL by inhbitiing hepatic secretion of VLDL and suppressing mobilization of FA
Clofibrate and gemifibrozil
promote rapid turnover of VLDL by activating LPL, gemfibrozil inhibits VLDL secretion
Probucol
reduce plasma cholesterol level but no effect on TG, Act via blockage of intestinal cholesterol transport, HDL cholesterol levels reduced
Statins
inhibit regulatory step in biosynthesis of cholesterol (HMG CoA reductase); lower serum cholesterol and LDL cholesterol by inhibition of hepatic cholesterol syn by up-regulating LDL receptor activity
Lipoproteinemia class IIA
Familail hypercholesterolemia: Defective LDL receptors or mutation oin ligand region of apo B-100. Elevated LDL levels and hypercholesterolemia, resulting in atherosclerosis and coronary disease.
Lipoproteinemia class IV
Familial hypertriacylglyerolemia: Overporduction of VLDL often associated with glucose intolerance and hyperinsulinemia. Cholesterol levels rise with the VLDL concentration. LDL and HDL usually subnormal. Often with CHD, Type II diabetes, obesity, alcoholism, and progesteronal hormones.
