Embed Size (px)
Citation preview
AtheroReversa MiceSwitching 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–/–Apob100/100
Ldlr–/–Apob+/+
Ldlr–/–Apob+/+
Cholesterol Distribution in the Plasma Mouse Aortas
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 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:
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
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) (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—
Absent Lipoprotein Production after pI-pC Injections
+pI-pC
No pI-pC
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
0
100
200
300
400
500
600Cholesterol Triglycerides
mg/dl
0
20
40
60
80
100
120
Chow Chow High-fat High-fat
No pI-pC +pI-pC
Strikingly Reduced Plasma Lipid Levels after Inactivation of Mttp
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-pC+pI-pC
Quantitative real-time PCR
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.
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
TriglyceridesCholesterol
mg/dl
Days after pI-pC
Size Distribution of Plasma Lipoprotein Particles after Administration of pI-pC
Ldlr–/–Apob100/100
Reversa mice, no pI-pC
Reversa mice, +pI-pC
