Lipoproteins Lecture for 1st year MBBs by Dr Sadia Haroon
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Transcript of Lipoproteins Lecture for 1st year MBBs by Dr Sadia Haroon
Lecture 4 – March 17, 2010
LIPIDS: LIPOPROTEINS/TRANSPORT
General Features of Lipoproteins
Apolipoproteins: specific lipid-binding proteins that attach to the surface intracellular recognition for exocytosis of the nascent particle after
synthesisactivation of lipid-processing enzymes in the bloodstream, binding to cell surface receptors for endocytosis and clearance.
Main lipid components: triacylglycerols, cholesterol esters, phospholipids. Major lipoproteins:
chylomicronsvery low density lipoproteins (VLDL)low density lipoproteins (LDL) high density lipoproteins (HDL)
Subfraction: intermediate density lipoproteins (IDL)
Electrophoretic mobility (charge):HDLs = lipoproteinsLDLs = -lipoproteins VLDLs = pre- lipoproteins (intermediate between and mobility).
Figure 1. Model of low density lipoprotein. Other lipoproteins have a similar structure differing in the core content of lipid and the type of apoproteins on the surface of the molecule
0%
20%
40%
60%
80%
100%
Chylo-microns
VLDL LDL HDL
Lipoprotein Type
Composition
C
P
T
C
P
T
T
P
C
C P
T
Figure 2. The major classes of lipoproteins and their relative content of triacylglycerol (T), cholesterol (C) and protein (P).
LIVER
ApoB48 aids with chylo-micron assembly
Lymph system:Chylomicrons to capillaries via lymph
I N T E S T I N E
non-hepatic tissuesnon-hepatic tissues
C E C EC EC E C E
C EC E C E
C E
Figure 3. Exogenous pathway of lipid transport. Chylomicrons carry dietary fatty acids to tissues
and the remnants take cholesterol to the liver
Nascent chylo-microns acquire apo CII (C) and E (E) from HDL
chylomicron interacts with lipoprotein lipase removing FFA
Chylomicron (or VLDL)
Apo CIILIPOPROTEIN LIPASE
PolysaccharideChain
EndothelialSurface of cell
Triacylglycerolin core
Free fatty acids
Glycerol
To Liver
Free fatty acidsIn cellulo (muscle & adipose)
Capillary
Figure 4. Lipoprotein lipase action on chylomicron triacylglycerol (an identical reaction occurs with VLDL)
LIVER
ApoB48chylomicron remnants lose CII to HDL
non-hepatic tissuesnon-hepatic tissues
C E C E
E
E
E
EC
C
C
C EC E C E
C E
EE E
Liver: apo E receptor takes up remnants to deliver cholesterol
Figure 3. Exogenous pathway of lipid transport. Chylomicrons carry dietary fatty acids to tissues and the remnants take cholesterol to the liver
Lymph system:
I N T E S T I N E
C E C EC E
chylomicron acquires apo CII (C) and E (E) from HDL
chylomicron interacts with lipoprotein lipase removing FFA
B100 (B) helps assemble and export nascent VLDL
LIVER
nascent VLDL acquires apo CII (C) and apo E (E) from HDL
C EC E C E C EC E C EC E
C EC E
B B
B
BB
B BB
bile acids
HDL scavenge cholesterol
C EC E
B BB
Figure 5. The liver-directed endogenous pathway of lipoprotein metabolism.
non-hepatic tissuesnon-hepatic tissues
LPL hydrolyze TAGs; FFA uptake; LDL circulate to tissues
apo B100 on LDL bind to receptor
LDL taken into the cell to deliver cholesterol
CII and E release to HDL
Apo E binds liver receptor
Cholesterol uptake; excreted as bile acids
Nascent Chylomicron Assembly in Gut Mediated by B48
Nascent HDL Assembled in liver Loans apo E/ apo CII
to nascent chylomicrons
Mature Chylomicron Apo E and CII
added from HDL
Lipoprotein Lipase capillary walls hydrolyzes TAG deliver FFA into adipose/muscle
Mature HDL CE from peripheral cells via
LCAT activated by apo A1 Apo CII returned by
chylomicrons
Chylomicron Remnant from mature chylomicron apo CII returned to HDL
Chylomicrons: Exogenous Pathway
HDL: Both Pathways
apo CII
Triacylglycerol Cholesterol ester
Phospholipid
E
CII A1
E B48 CII
A1
E
CII
B48
apo E & CII from HDL
B48
adipose &muscleFFA
CII
CII
CII
CII
E
EE
E
CII
CII
Fig. 6 Chylomicron Processing and Interface with HDL
Mature Chylomicron Apo E and CII
added from HDL CII activates LPL
B48
Lipoprotein Lipase capillary walls hydrolyzes TAG deliver FFA into adipose/muscle
LDL from mature VLDL
A1
CII
B100
Nascent VLDL Assembly in Liver Mediated by B100
VLDL/LDL: Endogenous Pathway
HDL: Both Pathways
E
CIIA1
Fig. 6 VLDL/LDL Processing and Interface with HDL
Mature VLDL Apo E and CII
added from HDLE
CII
B100
apo CII & E from HDL
EE
E
E
CII
CII
CII
adipose &muscle FFA
apo CII + EE
CII
EEE
CII
CII
Mature HDLApo CII/E returned by VLDL
B100
B100
Mature VLDL Apo E and CII
added from HDL CII activates LPL
E Receptor
Mature HDL
CE Metabolism Bile acids
Chylomicron Remnant
E Receptor
B100receptor
LDL
Fig. 6 Clearance of Cholesterol by Liver from Chylomicron Remnants, HDL and LDL
E
B48
E
B48
E
B48
A1
EA1
E
A1
E
B100
B100
B100
Pathogenesis
Oxidized LDL
1. Uptake by "scavenger receptors" on macrophages that invade artery walls; become foam cells2. Elicits CE deposition in artery walls3. Atherosclerosis/CAD can develop
Figure 6. Consequence of Oxidized LDL Formation
Oxidation of LDL
LDL
free pool ofcholesterol
LDLCE
endocytosis
late endosome
ACEHCE cholesterolB100 amino acids
NPC-1 mediated transfer
Cholesterol Esterase
Cholesterol metabolism to bile acids or steroids
Golgi
Cholesterol release for transport to liver
MembraneCholesterol
ACAT (stimulated by cholesterol)
CE CE
CE stored in droplets
CERPL C A T
Apo A1 receptor
A1
CII
EA1
ECIICE in nascent HDL
Apo A1 binds to receptor, activates CERP to pump out cholesterol, and LCAT to esterify cholesterol
Mature HDL:Cleared by liver
ooo
clathrin-coated pit
LDL receptor
ooo
vesicle
Recycling of receptor
transport vesicle- lysosome fuse forming late endosome
sorting endosome: ligand/receptor dissociation
lysosome
Figure 7. Cellular cholesterol uptake, metabolism and release.
ReverseCholesterolTransport
Recycling of receptor and clathrin
Lipoprotein classes:
Lipo-protein
Source Apo Proteins in
Mature
Protein:Lipid/Major (minor) Lipid
Transported
Function
Chylo-microns
gut B48, CII*, E*
1:49triacylglycerol (CE)
Dietary:FFA Adipose/muscleCE Liver via remnants
VLDL liver B100, CII*, E*
1:9triacylglycerol (CE)
Synthesized:FFA adipose/muscleCE LDL
LDL blood B100 1:3cholesterol ester
CE to liver (70%) and peripheral cells (30%)
HDL liver A1, CII, E("ACE")
1:1cholesterol ester
supplies apo CII, E to chylomicrons and VLDL; mediates reverse cholesterol transport
Functions of Apolipoproteins & Enzymes in Lipid Transport/Processing
Protein (Enzyme)
Site of Action Activator Function
LPL (Enzyme) capillary walls apo CIIexcises FFA from TAGs in chylomicrons and VLDLs for adipose and muscle
ACAT (Enzyme) inside cells free choles cholesterol ester storage
LCAT (Enzyme) blood apo A1cholesterol extraction from cells HDL carries CE for liver clearance (to bile acids)
CERPplasma
membrane
apo A1 (choles.Induced)
flips cholesterol (and lecithin) to outer layer of lipid bilayer for LCAT action in blood
TTPintestine/liver
smooth ERnone loads TAGs onto B48 (gut) and B100 (liver)
Apo A1blood, plasma
membranenone
activates LCAT and CERP; binds to apo A1 receptors on cells requiring cholesterol extraction
Apo B48 Gut none export of chylomicrons from intestinal cells
Apo B100 Various cells none ligand for LDL receptor; export of liver VLDL
Apo CII capillary walls none activates lipoprotein lipase
Apo E liver none receptor ligand - clears remnants, IDL, and HDL