International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

G22. Genetic Backgrounds Determine the Severity of Hypercholesterolemia, Atherosclerosis and Xanthoma in Spontaneously Hyperlipidemic (SHL) Mice

Yoshibumi Matsushima1, Takanobu Sakurai2, Ayumi Ohoka2, Tatsuya Ohnuki2, Norihiro Tada2, Yukiko Asoh1, Masayoshi Tachibana1
1Research Institute, Saitama Cancer Center Research Institutes
2Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd.

Spontaneously hyperlipidemic (SHL) mice are Japanese wild mice (Mus musculus molossinus KOR) with gross disruption of the gene for apolipoprotein E. These SHL mice (hereafter KOR-Apoeshl) are superhypercholesterolemic and develop severe xanthoma, but their atherosclerosis is relatively mild compared with Apoe knock out mice. First, we tested whether this distinction between KOR-Apoeshl and Apoe knockout mice is due to additional mutation of the Apoc1 and/or Apoc2 genes, which localize adjacent to the Apoe gene, in KOR-Apoeshl. Southern blot analysis, however, found no gross disruption of these two genes. Next, we tested whether the phenotypic distinction is due to differences in the genetic background in two strains of apolipoprotein E deficient mice. To this end, we established three lines of congenic SHL mice with a genetic background of C57BL/6, BALB/c or C3H/He mice, and named them, respectively, C57BL/6. KOR- Apoeshl (hereafter B6. KOR- Apoeshl), BALB/c. KOR-Apoesh (C.KOR-Apoeshl ) and C3H/He.KOR-Apoesh (C3.KOR-Apoeshl). Hypercholesterolemia was most severe in KOR-Apoeshl followed by others in a following manner; KOR- Apoeshl >> C3.KOR-Apoeshl > C.KOR-Apoeshl > B6.KOR-Apoeshl In contrast, atherosclerosis was most severe in B6.KOR-Apoeshl followed by the others in this manner: B6.KOR-Apoeshl > C.KOR-Apoeshl >> C3.KOR-Apoeshl KOR-Apoeshl. This order, however, did not match that in xanthoma, which was highly prominent in KOR-Apoeshl but mild in B6.KOR-Apoeshl, C.KOR-Apoeshl and C3.KOR-Apoeshl. These clear distinctions suggest that the severity of each of the phenotypes, i.e., hypercholesterolemia, atherosclerosis and xanthoma, is determined by distinct genetic backgrounds independently. Japanese wild mice possibly have suppressor genes for atherosclerosis, while laboratory mice have suppressor genes for xanthoma/hyperlipidemia. Or enhancer genes for each phenotype may exist. Prominent distinctions of the phenotypes between SHL mice with the genetic background of wild mice, and those with that of laboratory mice background are useful for identification of the genes responsible for atherosclerosis, hypercholesterolemia and xanthoma that are due to apolipoprotein E deficiency.

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