Abstract
We report the identification and partial characterization of polymorphisms among inbred strains of mice affecting several aspects of the expression of apolipoproteins B and E (apoB and apoE), the major proteins of low density lipoproteins (LDL) and very low density lipoproteins (VLDL). These polymorphisms include differences in the levels of the lipoproteins and apolipoproteins on both chow and high fat diets, differences in their response to a high fat diet challenge, and differences in the relative levels of the two molecular weight species of apoB. Although most strains exhibited a large increase in plasma LDL and VLDL in response to a high fat diet, the levels of apoB and apoE mRNA were either unaffected or, in some cases, decreased slightly. Also, the levels of apoB and apoE mRNA were not correlated among strains with the levels of the apolipoproteins in plasma, suggesting that genetic control occurs primarily at the level of lipoprotein catabolism. Elucidation of the precise mechanisms involved in the differences will require genetic analysis. Toward this end, we have identified DNA polymorphisms for apoB and apoE and have used these in segregation analysis to determine the chromosomal locations of the apoB and apoE structural genes in mice. The gene for apoB, designated Apob, resides in the proximal region of chromosome 12 linked to genes for ribosomal RNA and aryl hydrocarbon hydroxylase. The gene for apoE, designated Apoe, is located on chromosome 7, linked to genes for glucose phosphate isomerase and peptidase 4. Previously, we mapped the structural genes for apolipoproteins A-I and A-II to mouse chromosomes 9 and 1, respectively, and thus, the four loci encoding mammalian apolipoproteins have now been located in the mouse. These loci are homologous to the loci encoding apolipoproteins in humans as judged by the conservation of linked markers. A correlation was observed between a unique apoB allele and "responsiveness" to a high fat diet challenge. There were no obvious associations of apoB, apoE, or LDL/VLDL phenotypes or genotypes with diet-induced atherosclerosis among strains surveyed. These results clarify the organization and regulation of the genes for apoB and apoE, and they provide information about the naturally occurring polymorphisms affecting their expression.
Highlights
We report the identification and partial characterization of polymorphisms among inbred strains of mice affecting several aspectsof the expression of apolipoproteins B and E(apoB and apoE), the major proteins of low density lipoproteins (LDL)and verylow density lipoproteins (VLDL)
Mice exhibit polymorphisms affecting the levels and structures of plasma lipoproteins, providing an opportunity to identify the genetic and molecular factors controlling lipoprotein expression [1].Among the genes likelyto contribute to these polymorphisms are those for apolipoproteins, a family of proteins functioning as the structuralcomponents of lipoproteins, cofactors for lipases, and ligands for receptor-mediated catabolism of lipoproteins [2]
We previously described the identification of genes controlling the expression of high density lipoproteins (HDL)’ [3, 4], and wenow reportthe identification and partial analysis of polymorphisms for the two major apolipoproteins of low density lipoproteins (LDL) and very low density lipoproteins (VLDL), apolipoproteins B and E
Summary
Filters were hybridized at 42 “C for Animals and Diets-Mice were obtained from Jackson Laboratory, Bar Harbor, ME. The strains usedwere A/J (A), AKR/J (AKR), BALB/c(JBALB/c), C3H/HeJ (C3H), C57BL/6(JC57BL/6), C57L/J(C57L),C58/J (C58), DBA/2J(DBA/2),IS/CamEi (IS), inbred Mus nwlossinus, MOLF/Ei (MOLF), NZB/BlNJ (NZB), 24 h and washed in 1 X SSC at room temperature, followedby 4 washes (10 mineach) in 0.1 X SSC at 50 “C.The relative abundance of each mRNA in tissue RNA preparations was calculated by quantitative scanning densitometry of filter autoradiograms. PERU/AtteckEi (PERU), LT/Sv (LT), SJL/J (SJL), SK/CamEi (SK), SM/J (SM), SWR/J (SWR), 129/J [129],and various recom-
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