ApoC-III and TG-rich VLDL Lipolysis - LipidCenter · ApoC-III is an important apolipoprotein that...
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ApoC-III is an important apolipoprotein that is an independent risk factor for CHD. When present in increased amounts it is thought to interfere with binding of apoC-II to lipoprotein lipase and to prevent binding of apoB particles (LDL and VLDL) to LDL receptors. Both of these actions will delay the catabolism of TG-rich apoB containing lipoproteins, which can lead to increased blood viscosity, decreased flow-mediated dilation and elevated apolipoprotein B levels. ApoC-III exists in three isoforms C-III 0 , C-III 1 and C-III 2 contributing to 10, 55 and 35% respectively of total apoC-III levels. The isoforms are separated by their degree of sialylation (non, mono and di-sialylated), a Golgi mediated process. Sialylation is not related to lipid concentrations. ApoC-III 1 and C-III 2 are associated with the metabolic syndrome. Studies suggests that the di-sialylated CIII 2 isoform has high affinity for VLDL which makes the TG-rich particle particularly resistant to lipolysis. The increased residence time allows for CETP mediated transfer of TG to LDL and HDL and their subsequent lipolysis by hepatic lipase creating small LDL and HDL. Thus LDL particle size may be related to apoC-III sialylation and especially the apoC-III 2 isoform. This hypothesis may help explain the presence of numbers of small LDL in those with very variable plasma TG concentrations. ApoC-III and TG-rich VLDL Lipolysis Lipoprotein Lipase (LPL) Apo CII If present in excess amounts, Apo CIII blocks LPL from the ligand Apo CII Apo E Apo CIII Lipoprotein B-CIII or LpB-CIII
Transcript of ApoC-III and TG-rich VLDL Lipolysis - LipidCenter · ApoC-III is an important apolipoprotein that...
ApoC-III is an important apolipoprotein that is an independent risk factor for CHD. When present in increased amounts it is thought to interfere with binding of apoC-II to lipoprotein lipase and to prevent binding of apoB particles (LDL and VLDL) to LDL receptors. Both of these actions will delay the catabolism of TG-rich apoB containing lipoproteins, which can lead to increased blood viscosity, decreased flow-mediated dilation and elevated apolipoprotein B levels. ApoC-III exists in three isoforms C-III0, C-III1 and C-III2 contributing to 10, 55 and 35% respectively of total apoC-III levels. The isoforms are separated by their degree of sialylation (non, mono and di-sialylated), a Golgi mediated process. Sialylation is not related to lipid concentrations. ApoC-III1 and C-III2 are associated with the metabolic syndrome. Studies suggests that the di-sialylated CIII2 isoform has high affinity for VLDL which makes the TG-rich particle particularly resistant to lipolysis. The increased residence time allows for CETP mediated transfer of TG to LDL and HDL and their subsequent lipolysis by hepatic lipase creating small LDL and HDL. Thus LDL particle size may be related to apoC-III sialylation and especially the apoC-III2 isoform. This hypothesis may help explain the presence of numbers of small LDL in those with very variable plasma TG concentrations.
ApoC-III and TG-rich VLDL Lipolysis
Lipoprotein Lipase (LPL)Apo CII
If present in excess amounts, Apo CIII blocks
LPL from the ligand Apo CII
Apo E
Apo CIII
Lipoprotein B-CIII or LpB-CIII
ApoCIII and TG-rich VLDL Lipolysis
Lipoprotein Lipase (LPL)
Apo CIII
Apo CIII blocks LPL from the ligand Apo CII
Lipolysis of the TG-rich VLDL particle is delayed
Plasma TG levels ↑
LpB-CIII
Adipocyte & Myocyte (skeletal, cardiac)
VLDL Receptor or LRP
ApoCIII and LDL Particles
Apo B
Apo CIII, if present blocks Apo B
recognition by LDLr
LDLr Hepatocyte
LDL (Lp B-CIII)
These patients have increased
ApoCIII/ApoB ratios
• LDL receptors (LDLr) expressed
• LDL particles have delayed clearance and increased circulation time
Scavenger Receptor
?
TG-rich Lipoproteins and InflammationMacrophage “Foam Cell”
Cholesteryl ester
Free Cholesterol
CE
Peter Libby Circulation Research 2007;100:299-3011
Oxidation of LDL releases bioactive lipids that incite
inflammation in vascular tissues
Binding & internalization of LRP activates P38 MAP kinase &
NFκB
ApoC-III LP also activate proinflammatory functions of EC via NFκB recruitment of
leukocytes
NF-κB
m-RNA
?
LDL Receptor Protein (LRP)
oxLDL
Proinflammatory proteins
(eg VCAM-1)
P38 MAPK
LDL
VLDL
VLDL CIII
HDL
Oxidized phospholipids
CETP
ApoC-III, Triglycerides and IR
Hermes Florez et al. Atherosclerosis 188 (2006) 134–141
25.00 1 2 3 4 5
0
10
20
30
40
26.0
27.0
28.0
29.0
0 1 2 3 4 5
p<0.001
LDL
Peak
Par
ticle
Dia
met
er
Number of Metabolic Syndrome Components
LDLp
pd/T
GMean of LDL particle size according to the number of metabolic syndrome
components.
Data normalized for triglyceride values (figure inset) show statistically significant trends for the
LDL–PPD/TG ratio (P < 0.0001).
ApoC-III, Triglycerides and IR
Hermes Florez et al. Atherosclerosis 188 (2006) 134–141
8
0 1 2 3 4 5
80
120
40
10
12
20
24
0 1 2 3 4 5
p<0.0001apoC
-III (
mg/
dL)
Number of Metabolic Syndrome Components
apoC
-III/T
G
Mean of apoC-III concentration according
to the number of metabolic syndrome
components.
Data normalized for TG values (figure inset) show
statistically significant trends for the apoC-III/TG
ratio (P < 0.0001).
160
200
16
18
22
14
ApoC-III, Triglycerides and IR
0
0.5
1.0
1.5
2.0
2.5
3.0
African Americans Hispanics Caucasians
P = 0.012 (diabetes effect); p = 0.017 (HOMA IR Effect)
NGT-Lo-HOMA-IR
NGT-Hi-HOMA-IR
DM-Lo-HOMA-IR
DM-Hi-HOMA-IR
Trig
lyce
rides
(mg/
dL)
Hermes Florez et al. Atherosclerosis 188 (2006) 134–141
ApoC-III, Triglycerides and IR
Hermes Florez et al. Atherosclerosis 188 (2006) 134–141
NGT-Lo-HOMA-IR
NGT-Hi-HOMA-IR
DM-Lo-HOMA-IR
DM-Hi-HOMA-IR
African Americans
Apo
lipop
rote
in C
-III (
mg/
dL)
Hispanics Caucasians
P = 0.02 (diabetes effect); p = 0.005 (HOMA IR Effect)
02468
101214161820
These results suggest that higher apo C-III may contribute to the increased cardiovascular risk in subjects with insulin resistance and type 2 diabetes
through its effects on triglycerides and LDL particle size.
