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AtheroReversa Mice
Switching Off Hypercholesterolemia
without
Hypolipidemic Drugs or Changing the Diet
Ldlr–/–
Apob100/100
Mice: High LDL Cholesterol
Levels and Severe Atherosclerosis on a Chow
Diet
Ldlr–/–Apob100/100
Ldlr–/–...
The Role of Microsomal Triglyceride
Transfer Protein (MTP) in Lipoprotein
Assembly
That we could eliminate LDL cholesterol from
Ldlr–/–
Apob100/100
mice by inactivating Mttp (the
gene for microsomal trigly...
Reversing Hypercholesterolemia
in AtheroReversa Mice
Ldlr–/–
Apob100/100
Mttpfl/fl
Mx1-Cre+/+
Mice
Ldlr–/–
Apob100/100
Mtt...
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Liver Mttp Expression
(real-time PCR)
No pI-pC +pI-
pC
(Mttpfl/fl
)
Strikingly Reduced Mttp ...
Absent Lipoprotein Production after pI-pC
Injections
+pI-pC
No pI-pC
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
6 0 0
Cholesterol
mg/dl
Cho
w
High-
fat
No pI-pC
+pI-pC
Strikingly Reduced Plasma Lipid
Le...
0
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
6 0 0
Cholesterol Triglycerides
mg/dl
0
20
40
60
80
100
120
Cho
w
Cho
w
High-fatHigh-
fat
...
Virtual Absence of LDL
Cholesterol after Inactivation of
Mttp
mg/dl
Cholesterol
A Striking Decrease in
Triglycerides in both the VLDL
and LDL Fractions
mg/dl
Cholesterol Triglycerides
No pI-
pC
+pI-pC
Absence of Atherosclerosis in pI-pC–treated
Mice
Profound Changes in Gene
Expression in Aortas from pI-pC–
treated Mice
0.0
0.2
0.4
0.6
0.8
1.0
1.2
CD68 MCP-1 VCAM-1
No pI...
AtheroReversa
Mice
• High levels of LDL cholesterol can be
eliminated by “switching off” hepatic
lipoprotein production.
•...
Virtual Absence of LDL Cholesterol after
Inactivation of Mttp (High-fat Diet)
Cholesterol Triglycerides
mg/dl
Decrease in Plasma Lipid Levels
after the First Dose of pI-pC
Triglyceride
s
Cholesterol
mg/dl
Days after pI-pC
Size Distribution of Plasma
Lipoprotein Particles after
Administration of pI-pC
Ldlr
–/–
Apob
100/100
Reversa mice, no pI-...
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187 athero reversa mice

  1. 1. AtheroReversa Mice Switching Off Hypercholesterolemia without Hypolipidemic Drugs or Changing the Diet
  2. 2. Ldlr–/– Apob100/100 Mice: High LDL Cholesterol Levels and Severe Atherosclerosis on a Chow Diet Ldlr–/–Apob100/100 Ldlr–/– Apob100/100 Ldlr–/–Apob+/+ Ldlr–/–Apob+/+ Cholesterol Distribution in the Plasma Mouse Aortas
  3. 3. The Role of Microsomal Triglyceride Transfer Protein (MTP) in Lipoprotein Assembly
  4. 4. That we could eliminate LDL cholesterol from Ldlr–/– Apob100/100 mice by inactivating Mttp (the gene for microsomal triglyceride transfer protein) in the liver. Experimental Strategy: To generate Ldlr–/– Apob100/100 mice that are homozygous for a conditional Mttp allele and the inducible Mx1-Cre transgene. AtheroReversa Mice Hypothesis:
  5. 5. Reversing Hypercholesterolemia in AtheroReversa Mice Ldlr–/– Apob100/100 Mttpfl/fl Mx1-Cre+/+ Mice Ldlr–/– Apob100/100 Mttp∆/∆ Mx1-Cre+/+ Mice Cre Induction with pI-pC – High LDL Cholesterol – Absent LDL Cholesterol
  6. 6. 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Liver Mttp Expression (real-time PCR) No pI-pC +pI- pC (Mttpfl/fl ) Strikingly Reduced Mttp mRNA Levels and Plasma Apo-B100 Levels after Cre Induction Apo-B100 in the plasma (western blot) No pI-pC +pI-pC Apo-B100 —
  7. 7. Absent Lipoprotein Production after pI-pC Injections +pI-pC No pI-pC
  8. 8. 0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0 6 0 0 Cholesterol mg/dl Cho w High- fat No pI-pC +pI-pC Strikingly Reduced Plasma Lipid Levels after Inactivation of Mttp
  9. 9. 0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0 6 0 0 Cholesterol Triglycerides mg/dl 0 20 40 60 80 100 120 Cho w Cho w High-fatHigh- fat No pI-pC +pI-pC Strikingly Reduced Plasma Lipid Levels after Inactivation of Mttp
  10. 10. Virtual Absence of LDL Cholesterol after Inactivation of Mttp mg/dl Cholesterol
  11. 11. A Striking Decrease in Triglycerides in both the VLDL and LDL Fractions mg/dl Cholesterol Triglycerides
  12. 12. No pI- pC +pI-pC Absence of Atherosclerosis in pI-pC–treated Mice
  13. 13. Profound Changes in Gene Expression in Aortas from pI-pC– treated Mice 0.0 0.2 0.4 0.6 0.8 1.0 1.2 CD68 MCP-1 VCAM-1 No pI-pC +pI-pC Quantitative real-time PCR
  14. 14. AtheroReversa Mice • High levels of LDL cholesterol can be eliminated by “switching off” hepatic lipoprotein production. • Elimination of LDL cholesterol prevents atherosclerosis. • Model should be useful for analyzing regression of atherosclerosis.
  15. 15. Virtual Absence of LDL Cholesterol after Inactivation of Mttp (High-fat Diet) Cholesterol Triglycerides mg/dl
  16. 16. Decrease in Plasma Lipid Levels after the First Dose of pI-pC Triglyceride s Cholesterol mg/dl Days after pI-pC
  17. 17. Size Distribution of Plasma Lipoprotein Particles after Administration of pI-pC Ldlr –/– Apob 100/100 Reversa mice, no pI- pC Reversa mice, +pI-pC

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