Download - Difference in lipid metabolism and atherosclerosis among human, rodents, and WHHL / WHHLMI rabbits
Difference in lipid metabolism and
atherosclerosis among human,
rodents, and WHHL / WHHLMI rabbits
Exogenous Pathway Endogenous pathway
Lipoprotein metabolism in human and rabbits
(Modified after Goldstein et al. N Engl J Med 1983; 309:288-286)
Dietary lipid
Bile acids+
Cholesterol
Intestine Liver
ChylomicronChylomicron
remnants
Remnant receptors
Lipoprotein lipase
Capillary
B-48B-48E
EC
apoB editing enzyme
LDL
LDL receptors
Peripheral tissued
IDLVLDL
Lipoprotein lipase
Capillary
B-100 B-100
B-100
E EC
LDL receptors
HDL
LCAT
CETPCETP
E A
Plasma
Exogenous pathway Endogenous pathway
Dietary lipids
Bile acids+
Cholesterol
intestine LiverPeripheral
tissues
HDLChylomicron Chylomicron
remnants
Remnant receptors
Lipoprotein lipase Lipoprotein lipase
capillary Capillary LCAT
B-48B-48 B-100B-100
B-100
EEC
CETPCETP
E A
LDLreceptors
Plasma
☓ ☓
apoB editing enzymeapoB editing enzyme
Lipoprotein metabolism in mice and rats
LDL
LDL receptors
VLDL
CE
IDL
EEEC
B-48
IDL
B-48
VLDL
Exogenous pathway Endogenous pathway
Dietary lipids
Bile acids+
Cholesterol
intestine LiverPeripheral
tissues
HDLChylomicron Chylomicron
remnants
Remnant receptors
Lipoprotein lipase Lipoprotein lipase
capillary Capillary LCAT
B-48B-48 B-100B-100
B-100
EEC
CETPCETP
E A
LDLreceptors
Plasma
☓ ☓
apoB editing enzymeapoB editing enzymeLDL
LDL receptors
VLDL
CE
IDL
EEEC
B-48
IDL
B-48
VLDL
☓ ☓
☓
☓☓ ☓ ☓
☓
☓
Lipoprotein metabolism of ApoE KO
Human
240
190
140
90
40
-1015 17 19 21 23 25 27 29 31 33 35 37 15 17 19 21 23 25 27 29 31 33 35 37 15 17 19 21 23 25 27 29 31 33 35
Elusion time (min) Elusion time (min) Elusion time (min)
Wild mice
170
150
130
110
90
70
50
30
10
-10
LDLLDL HDL
HDLVLDLChylomicron remnants
VLDL
VLDL + Chylomicron remnants
ApoE KO mice
Data from Skylight Biotech Inc.
(mV) (mV) (mV)
Lipoprotein profiles of human and mice with HPLC
HDL
Free Glycerol
Free Glycerol
Free Glycerol
1.25% Cholesterol-fed
LDLR-KO mice
0 10 20 30
Fraction Number
Ishibashi S, et al. (JCI 1994; 93:1885-93)Total cholesterol triglyceride
Standard diet
Exogenous pathway Endogenous pathway
Dietary lipids
Bile acids+
Cholesterol
Intestine Liver LDL
LDL receptors
Peripheral tissues
HDLVLDLChylomicron remnants
Remnant receptors
Lipoprotein lipase Lipoprotein lipase
Capillary CapillaryLCAT
B-48B-48 B-100 B-100
B-100
EE
E EC C
CETPCETP
E A
LDLreceptors
Plasma
Lipoprotein metabolism of WHHL / WHHLMI rabbits
apoB editing enzyme
IDLChylomicron
Human
240
190
140
90
40
-1015 17 19 21 23 25 27 29 31 33 35 37 15 17 19 21 23 25 27 29 31 33 35 37
Elusion time (min) Elusion time (min)
VLDL
VLDL
ApoE KO mice
Data from Skylight Biotech Inc.
(mV) (mV)
Lipoprotein profiles in the plasma
of human apoE-KO mice, and WHHLMI rabbits
HDL
FreeGlycerol
FreeGlycerol
Elusion time (min)
LDL HDLVLDL
WHHLMI rabbit
FreeGlycerol
HDL
LDL
Total cholesterol triglyceride
Plasma CETP activity of WHHL rabbits
Son YC, et al. (Arteriosclerosis 1986; 6: 345-351)
Coronary plaque of human(Falk E, Br Heart J 1983; 50: 127-134)
Coronary lesion of ApoE-KO/ LDLR-KO mouse fed high fat diet ( Masson’s Trichrome stain )Caligiuri G, et al. PNAS 1999; 96: 6920-6924
Coronary lesion of ApoE-KO /SRBI-KO mice fed standard chow ( Masson’s Trichrome stain )
Braun A, et al. Cir Res 2002; 90: 270-276
40 m
Coronary lesion of LDLR-KO mice fed high fat diet ( H&E stain )Ishibashi S, et al. JCI 1994; 93: 1885-1893
Coronary lesions of mouse models were different from human coronary plaques.
(Falk E, Br Heart J 1983; 50: 127-134)
Ruptured coronary plaque of human
Vulnerable coronary plaque of WHHLMI rabbit
Azan-Mallory stain RAM-11 immunostaining
Elastic van Gieson stain 1A4 immunostaining
(modif. after Shiomi M et al, ATVB; 2003; 23: 1239-1244 )
Macrophageaccumulation
Vulnerableplaque
Low SMCs
Thin fibrous
cap
Lipiddeposits
(modif. after Davies MJ: Circulation 94: 2013-2020, 1996)
Statin increases cholesterol synthesis in rats
(A) Day 0
Fujioka T, et al. (BBA 1995; 1254: 7-12)
Pravastatin
Pravastatin
Statin up-regulates HMG-CA reductase activity and fatty acids synthesis in rats
Fujioka T, et al. (Eur J Pharmacol 1997; 328:235-239)
(modif. after Shiomi M et al, ATVB 1995; 15: 1938-1944)
(mg/
dl)
(mg/
dl)
Whole plasma cholesterol LDL cholesterol
Plasma Lipid Levels and Degree of Atherosclerosis of Mature WHHL Rabbits Treated with Pravastatin
- 17% (vs Placebo)
P<0.05
- 14% (vs.Placebo)
P<0.05
Control at the start (10 months old)
Placebo treatment from 10 to 22 months old
Pravastatin treatment from 10 to 22 months old
LDL
Ilium and Liver Ilium
Main lipoproteins
ApoB of VLDL
ApoB Editing enzyme
CETP
HTGL
Dietary fats /cholesterol
Atherosclerosis
Inflammatory marker
Hypolipidemic effects of statins
Mice and Rats Human WHHLMI
Summary of species difference in lipid metabolism and atherosclerosis
HDL, VLDL, chylomicron remnants
apoB-48 & apoB-100 apoB-100
none Yes
Unbound to membrane Bound to membrane
Resistance Susceptible
No effects or Increase in cholesterol
apoB-100
Ilium
Yes
Bound to membrane
Spontaneous
Effective
Serum Amyloid P component
SAP CRP
Resistance SusceptibleLipid–rich/Collagen-poor Various lesions
SpontaneousVarious lesions
CRP
Effective
LDL
Different phenotypes manifested in mouse and rabbits after the same gene transfer
Genes transferred Mice Rabbits
Lecitin:cholesterol acyltransferase
Hepatic lipase
apoE3
15-lipoxygenase
Apolipoprotein(a)
Lipoprotein lipase
CRP
(after modified by Koike T & Fan J, Laboratory Animal Technology and Science 2005; 17: 91-96)
No changes in Decrease in visceral fat visceral fat
unbound to apoB Boundnd to apoB
Pro-atherogenic Anti-atherogenic
Pro-atherogenic Anti-atherogenicPro-atherogenic Anti-atherogenicAnti-atherogenic Pro-atherogenic
No function Function
HumanWHHL /WHHLMIrabbits
≒≠
Difference in lipid metabolism, atherosclerosis, and the effects of statins
among human, rodents, and WHHL / WHHLMI rabbits
Mice and Rats(Including
transgenic and KO animals)
Thank you very much for your attention!