Abstract |
To establish low density lipoprotein receptor (LDLR) mutant rats as a hypercholesterolemia and atherosclerosis model, we screened the rat LDLR gene for mutations using an N-ethyl-N-nitrosourea mutagenesis archive of rat gene data, and identified five mutations in its introns and one missense mutation (478T>A) in exon 4. The C160S mutation was located in the ligand binding domain of LDLR and was revealed to be equivalent to mutations (C160Y/G) identified in human familial hypercholesterolemia (FH) patients. The wild type, heterozygous, and homozygous mutant rats were fed a normal chow diet or a high fat high cholesterol (HFHC) diet from the age of 10 weeks for 16 weeks. The LDLR homozygous mutants fed the normal chow diet showed higher levels of plasma total cholesterol and LDL cholesterol than the wild type rats. When fed the HFHC diet, the homozygous mutant rats exhibited severe hyperlipidemia and significant lipid deposition from the aortic arch to the abdominal aorta as well as in the aortic valves. Furthermore, the female homozygous mutants also developed xanthomatosis in their paws. In conclusion, we suggest that LDLR mutant rats are a useful novel animal model of hypercholesterolemia and atherosclerosis.
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Authors | Makoto Asahina, Tomoji Mashimo, Michiyasu Takeyama, Ryuichi Tozawa, Tadatoshi Hashimoto, Akiko Takizawa, Masatsugu Ueda, Toshihiro Aoto, Takashi Kuramoto, Tadao Serikawa |
Journal | Biochemical and biophysical research communications
(Biochem Biophys Res Commun)
Vol. 418
Issue 3
Pg. 553-8
(Feb 17 2012)
ISSN: 1090-2104 [Electronic] United States |
PMID | 22293196
(Publication Type: Journal Article)
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Copyright | Copyright © 2012 Elsevier Inc. All rights reserved. |
Chemical References |
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Topics |
- Animals
- Atherosclerosis
(blood, genetics, pathology)
- Disease Models, Animal
- Female
- Hypercholesterolemia
(blood, genetics, pathology)
- Lipids
(blood)
- Male
- Mutation
- Rats
- Rats, Inbred F344
- Rats, Mutant Strains
- Receptors, LDL
(genetics)
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