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Difference in lipid metabolism and atherosclerosis among human, rodents, and WHHL / WHHLMI rabbits

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Difference in lipid metabolism and atherosclerosis among human, rodents, and WHHL / WHHLMI rabbits. Bile acids + Cholesterol. Dietary lipid. LDL receptors. LDL receptors. Intestine. Liver. LDL. Peripheral tissued. apoB editing enzyme. B-100. Remnant receptors. Chylomicron remnants. - PowerPoint PPT Presentation

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Page 1: Exogenous Pathway                             Endogenous pathway

Difference in lipid metabolism and

atherosclerosis among human,

rodents, and WHHL / WHHLMI rabbits

Page 2: Exogenous Pathway                             Endogenous pathway

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

Page 3: Exogenous Pathway                             Endogenous pathway

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

Page 4: Exogenous Pathway                             Endogenous pathway

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

Page 5: Exogenous Pathway                             Endogenous pathway

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

Page 6: Exogenous Pathway                             Endogenous pathway

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

Page 7: Exogenous Pathway                             Endogenous pathway

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

Page 8: Exogenous Pathway                             Endogenous pathway

Plasma CETP activity of WHHL rabbits

Son YC, et al. (Arteriosclerosis 1986; 6: 345-351)

Page 9: Exogenous Pathway                             Endogenous pathway

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.

Page 10: Exogenous Pathway                             Endogenous pathway

(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)

Page 11: Exogenous Pathway                             Endogenous pathway

Statin increases cholesterol synthesis in rats

(A) Day 0

Fujioka T, et al. (BBA 1995; 1254: 7-12)

Pravastatin

Pravastatin

Page 12: Exogenous Pathway                             Endogenous pathway

Statin up-regulates HMG-CA reductase activity and fatty acids synthesis in rats

Fujioka T, et al. (Eur J Pharmacol 1997; 328:235-239)

Page 13: Exogenous Pathway                             Endogenous pathway

(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

Page 14: Exogenous Pathway                             Endogenous pathway

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

Page 15: Exogenous Pathway                             Endogenous pathway

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

Page 16: Exogenous Pathway                             Endogenous pathway

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)

Page 17: Exogenous Pathway                             Endogenous pathway

Thank you very much for your attention!