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

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Presentation on theme: "Difference in lipid metabolism and atherosclerosis among human, rodents, and WHHL / WHHLMI rabbits."— Presentation transcript:

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

2 Exogenous Pathway Endogenous pathway Lipoprotein metabolism in human and rabbits (Modified after Goldstein et al. N Engl J Med 1983; 309: ) Dietary lipid Bile acids + Cholesterol Intestine Liver Chylomicron Chylomicron remnants Remnant receptors Lipoprotein lipase Capillary B-48 E E C apoB editing enzyme LDL LDL receptors Peripheral tissued IDL VLDL Lipoprotein lipase Capillary B-100 E E C LDL receptors HDL LCAT CETP E A Plasma

3 Exogenous pathway Endogenous pathway Dietary lipids Bile acids + Cholesterol intestine Liver Peripheral tissues HDL Chylomicron Chylomicron remnants Remnant receptors Lipoprotein lipase capillary CapillaryLCAT B-48 B-100 E E C CETP E A LDL receptors Plasma ☓ ☓ apoB editing enzyme Lipoprotein metabolism in mice and rats LDL LDL receptors VLDL C E IDL E E E C B-48 IDL B-48 VLDL

4 Exogenous pathway Endogenous pathway Dietary lipids Bile acids + Cholesterol intestine Liver Peripheral tissues HDL Chylomicron Chylomicron remnants Remnant receptors Lipoprotein lipase capillary CapillaryLCAT B-48 B-100 E E C CETP E A LDL receptors Plasma ☓ ☓ apoB editing enzyme LDL LDL receptors VLDL C E IDL E E E C B-48 IDL B-48 VLDL ☓ ☓ ☓ ☓ ☓ ☓ ☓ ☓ ☓ Lipoprotein metabolism of ApoE KO

5 Human Elusion time (min) Elusion time (min) Elusion time (min) Wild mice LDL HDL VLDL Chylomicron remnants VLDL VLDL + Chylomicron remnants ApoE KO mice Data from Skylight Biotech Inc. (mV) Lipoprotein profiles of human and mice with HPLC HDL Free Glycerol Free Glycerol Free Glycerol 1.25% Cholesterol-fed LDLR-KO mice Fraction Number Ishibashi S, et al. (JCI 1994; 93: ) Total cholesterol triglyceride Standard diet

6 Exogenous pathway Endogenous pathway Dietary lipids Bile acids + Cholesterol Intestine Liver LDL LDL receptors Peripheral tissues HDL VLDL Chylomicron remnants Remnant receptors Lipoprotein lipase Capillary LCAT B-48 B-100 E E E E C C CETP E A LDL receptors Plasma Lipoprotein metabolism of WHHL / WHHLMI rabbits apoB editing enzyme IDL Chylomicron

7 Human Elusion time (min) Elusion time (min) VLDL ApoE KO mice Data from Skylight Biotech Inc. (mV) Lipoprotein profiles in the plasma of human apoE-KO mice, and WHHLMI rabbits HDL Free Glycerol Free Glycerol Elusion time (min) LDL HDL VLDL WHHLMI rabbit Free Glycerol HDL LDL Total cholesterol triglyceride

8 Plasma CETP activity of WHHL rabbits Son YC, et al. (Arteriosclerosis 1986; 6: )

9 Coronary plaque of human (Falk E, Br Heart J 1983; 50: ) Coronary lesion of ApoE-KO/ LDLR-KO mouse fed high fat diet ( Masson’s Trichrome stain ) Caligiuri G, et al. PNAS 1999; 96: Coronary lesion of ApoE-KO /SRBI-KO mice fed standard chow ( Masson’s Trichrome stain ) Braun A, et al. Cir Res 2002; 90:  m Coronary lesion of LDLR-KO mice fed high fat diet ( H&E stain ) Ishibashi S, et al. JCI 1994; 93: Coronary lesions of mouse models were different from human coronary plaques.

10 (Falk E, Br Heart J 1983; 50: ) Ruptured coronary plaque of human Vulnerable coronary plaque of WHHLMI rabbit Azan-Mallory stain RAM-11 immunostaining Elastic van Gieson stain1A4 immunostaining (modif. after Shiomi M et al, ATVB; 2003; 23: ) Macrophage accumulation Vulnerable plaque Low SMCs Thin fibrous cap Lipid deposits (modif. after Davies MJ: Circulation 94: , 1996)

11 Statin increases cholesterol synthesis in rats (A) Day 0 Fujioka T, et al. (BBA 1995; 1254: 7-12) Pravastatin

12 Statin up-regulates HMG-CA reductase activity and fatty acids synthesis in rats Fujioka T, et al. (Eur J Pharmacol 1997; 328: )

13 (modif. after Shiomi M et al, ATVB 1995; 15: ) (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

14 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 Susceptible Lipid–rich/Collagen-poor Various lesions Spontaneous Various lesions CRP Effective LDL

15 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 Anti-atherogenic Pro-atherogenic No function Function

16 Human WHHL / WHHLMI rabbits ≒ ≠ 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)

17 Thank you very much for your attention!


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