187 athero reversa mice
TRANSCRIPT
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AtheroReversa MiceSwitching Off Hypercholesterolemia without
Hypolipidemic Drugs or Changing the Diet
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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
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The Role of Microsomal Triglyceride Transfer Protein (MTP) in Lipoprotein Assembly
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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 MiceHypothesis:
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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
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Liver Mttp Expression (real-time PCR)
No pI-pC +pI-pC (Mttpfl/fl) (Mttp/)
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—
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Absent Lipoprotein Production after pI-pC Injections
+pI-pC
No pI-pC
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0
100
200
300
400
500
600Cholesterol
mg/dl
Chow High-fat
No pI-pC +pI-pC
Strikingly Reduced Plasma Lipid Levels after Inactivation of Mttp
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0
100
200
300
400
500
600Cholesterol Triglycerides
mg/dl
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Chow Chow High-fat High-fat
No pI-pC +pI-pC
Strikingly Reduced Plasma Lipid Levels after Inactivation of Mttp
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Virtual Absence of LDL Cholesterol after Inactivation of Mttp
mg/dl
Cholesterol
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A Striking Decrease in Triglycerides in both the VLDL and LDL Fractions
mg/dl
Cholesterol Triglycerides
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No pI-pC
+pI-pC
Absence of Atherosclerosis in pI-pC–treated Mice
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Profound Changes in Gene Expression in Aortas from pI-pC–treated Mice
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CD68 MCP-1 VCAM-1
No pI-pC+pI-pC
Quantitative real-time PCR
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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.
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Virtual Absence of LDL Cholesterol after Inactivation of Mttp (High-fat Diet)
Cholesterol Triglycerides
mg/dl
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Decrease in Plasma Lipid Levels after the First Dose of pI-pC
TriglyceridesCholesterol
mg/dl
Days after pI-pC
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Size Distribution of Plasma Lipoprotein Particles after Administration of pI-pC
Ldlr–/–Apob100/100
Reversa mice, no pI-pC
Reversa mice, +pI-pC