These apoB38.9 mutant mice may be useful to study the genetic and molecular mechanism of apoB defects and lipid metabolism/liver fat accumulation, the relationship between hepatic steatosis and insulin resistance, the progression of advanced non-alcoholic fatty liver diseases (NAFLD), and atherosclerosis. In addition, all three congenic apoB38.9 strains (Stock No. 007679, Stock No. 007682, and Stock No. 007683) may be useful in conjunction with other apoB mutant mice, including Stock No. 002053 (apoB70), Stock No. 002876 (apoB48-only), and Stock No. 002877 (apoB100-only).
Gustav Schonfeld, Washington University School of Medicine
Mice homozygous for this apoB38.9 allele (apoB38.9/38.9) are viable with impaired fertility, bearing a premature stop codon at residue 1767 of the targeted gene. As a result, homozygous plasma shows a truncated apoB38.9 as the sole apoB protein. Plasma from heterozygous (apoB+/38.9) mice have reduced apoB100 and apoB48 compared to wildtype, with apoB38.9 representing 20% of total circulating apoB. This apoB38.9 truncation affects both apoB100 and apoB48 metabolism in mice, and mimics human Familial Hypobetalipoproteinemia (FHBL). Homozygous and, to a lesser extent, heterozygous mice exhibit symptoms of FHBL due to impaired lipoprotein export system/VLDL secretion, including elevated hepatic triglyceride (TG), cholesterol and free fatty acids (FFA), with decreased plasma TG and cholesterol. Because plasma and liver lipid profiles range from mild to severe in populations of heterozygous apoB38.9 mice on a mixed (C57BL/6J;129X1/SvJ) genetic background, apoB+/38.9 congenic mice were generated on three different inbred strains with characterized differences in liver fat: SWR/J (low liver TG strain, ~40mg/dL), C57BL/6J (medium liver TG, ~140mg/dL), and BALB/cByJ (high liver TG strain, ~200 mg/dL). All three apoB+/38.9 congenic strains exhibit significantly impaired hepatic TG secretion compared to their respective genetic backgrounds, with significant interactions observed between genetic background and apoB genotype for liver TG and FFA. BALB/cByJ-apoB38.9 mice (Stock No. 007683) exhibit the greatest hepatic TG and FFA increase (probably due to elevated hepatic TG synthesis rate). Despite having the lowest degree of hepatic steatosis among the three apoB+/38.9 congenic strains, SWR/J-apoB38.9 mice (Stock No. 007679) show insulin resistance, with BALB/cByJ-apoB38.9 mice exhibiting intermediate and C57BL/6J-apoB38.9 mice (Stock No. 007682) exhibiting the greatest insulin resistance. Additional comparisons between the three congenic strains reveal that C57BL/6J-apoB38.9 mice have significant increase of fatty acid synthesis rate compared to the other two congenic strains, while SWR/J-apoB38.9 mice show dynamic feedback regulation of fatty acids and TG synthesis and beta-oxidation in response to excessive hepatic TG accumulation. Gender dimorphism is observed; while BALB/cByJ-apoB38.9 males have reduced plasma cholesterol levels compared to wildtype males, females from all three apoB+/38.9 congenic strains have reduced plasma cholesterol compared to wildtype females. Male BALB/cByJ-apoB38.9 and C57BL/6J-apoB38.9 mice have significant reduction of liver TG synthesis compared to wildtype males, while SWR/J-apoB38.9 females show the same significant reduction. These apoB38.9 mutant mice may be useful to study the genetic and molecular mechanism of apoB defects and lipid metabolism/liver fat accumulation, the relationship between hepatic steatosis and insulin resistance, the progression of advanced non-alcoholic fatty liver diseases (NAFLD), and atherosclerosis. These apoB38.9 mutant mice may also be useful in conjunction with other apoB mutant mice, including Stock No. 002053 (apoB70), Stock No. 002876 (apoB48-only), and Stock No. 002877 (apoB100-only).
A targeting vector was designed (by site-directed mutagenesis) to delete nucleotide 5449 of the mouse apo B cDNA sequence (the deletion is predicted to produce a premature stop codon at the same position (i.e. residue 1767) as that occurring in the apo B-38.9 mutation of human familial hypobetalipoproteinemia (FHBL) subjects). This also inserted a loxP-flanked PGK-neo cassette within intron 24. The construct was electroporated into 129X1/SvJ-derived RW4 embryonic stem (ES) cells. Correctly targeted ES cells were transiently transfected with a Cre-expressing vector to remove the selection cassette (leaving a single loxP site in intron 24) and then injected into C57BL/6 blastocysts. The resulting chimeric males were bred to C57BL/6 females. Heterozygotes were then backcrossed to SWR/J inbred mice (see Stock No. 000689) for 8 generations prior to arrival at The Jackson Laboratory.
|Allele Name||targeted mutation 1.1, Zhouji Chen|
|Allele Type||Targeted (Humanized sequence)|
|Gene Symbol and Name||Apob, apolipoprotein B|
|Gene Synonym(s)||AI315052; Aa1064; Ac1-060; Apo B-100; ApoB-100; ApoB-48; FLDB; LDLCQ4; apoB-100; apoB-48; apob-100; apob-48; expressed sequence AI315052|
|Promoter||Apob, apolipoprotein B, mouse, laboratory|
|Strain of Origin||129X1/SvJ|
|Molecular Note||Deletion of nucleotide 5449 in exon 26 and a loxP-flanked PGK-neo cassette inserted into intron 24 were introduced to the gene via homologous recombination. This deletion mimics the ApoB-38.9 truncation mutation found in human familial hypobetalipoproteinemia (FHBL). The neo cassette was removed by transient expression of Cre recombinase in correctly targeted ES cells. Southern blot analysis confirmed the absence of the neo cassette in homozygous mutant mice; Western blot analysis showed a mutant protein product of similar size to the human ApoB-38.9 mutant protein.|
|Mutations Made By|| |
Zhouji Chen, Washington University School of Medicine
When maintaining a live colony, heterozygotes are bred to wildtype siblings or to SWR/J inbred mice (see Stock No. 000689). The donating investigator reports that homozygous mice are produced in reduced rates and are probably infertile.
When using the SWR.129X1(B6)-Apobtm1.1Zc/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #007679 in your Materials and Methods section.
|Heterozygous or Wild-Type for Apob<tm1.1Zc>|
The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided,
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