title: Hypercholesterolemia and atherosclerosis in low density lipoprotein receptor mutant rats.
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.
authors.affiliation: Takeda Pharmaceutical Company Ltd., Pharmaceutical Research Division, Kanagawa, Japan. Asahina_makoto@takeda.co.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Asahina
authors.forename: Tomoji
authors.initials: T
authors.lastname: Mashimo
authors.forename: Michiyasu
authors.initials: M
authors.lastname: Takeyama
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Tozawa
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Akiko
authors.initials: A
authors.lastname: Takizawa
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ueda
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Aoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuramoto
authors.forename: Tadao
authors.initials: T
authors.lastname: Serikawa
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008055:Lipids / Q000097:blood; D008297:Male; D009154:Mutation; D051381:Rats; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains; D011973:Receptors, LDL / Q000235:genetics*
chemical_list: D008055:Lipids; D011973:Receptors, LDL