Apoe⁴ Ldlr^h Ins2^C96Y mice harbor two humanized knock-in mutations, the human APOE*4 replacement allele (Apoe^{tm3(APOE*4)Mae}) and the human LDLR replacement allele (Ldlr^tm1(LDLR)Mae), along with the dominant type 1 diabetes mutation Akita (Ins2^Akita). Unless noted otherwise, the phenotypes below are for mice maintained on regular chow (~5% fat; <0.1% cholesterol).

The human APOE*4 replacement allele (Apoe⁴ or E4) expresses the human apoE4 isoform in place of the endogenous apoE protein. Under direction of the endogenous mouse apoE promoter/regulatory regions, human apoE4 expression is observed at physiological levels in the same temporal and spatial pattern observed in humans. Mice homozygous for human APOE*4 (Apoe^4/4) are viable and fertile with normal plasma lipid and lipoprotein profiles. Apoe^4/4 show mild retinal changes with aging. When maintained on high fat/cholesterol diet mirroring that consumed by humans, Apoe^4/4 exhibit increased susceptibility to atherosclerosis, impaired glucose tolerance, fat overload, amyloid beta immunoreactivity, degenerative changes in the retina and other metabolic defects.

The human LDLR replacement allele (Ldlr^h) has the promoter/regulatory regions and exon 1 (encoding only the signal peptide) from endogenous mouse Ldlr directing expression of a human LDLR sequence modified to have increased mRNA transcript stability; this results in expression of hLDLR protein in place of endogenous mouse Ldlr protein, with three-fold greater levels. Both homozygous human LDLR (Ldlr^h/h) mice and heterozygous human LDLR (Ldlr^h/+) mice are viable and fertile with a ~40% reduction in steady state plasma cholesterol. The reduction is primarily in the HDL cholesterol fraction, resulting in elevated non-HDL/HDL cholesterol ratio. The HDL cholesterol of Ldlr^h/+ mice is <50 mg/dl, and is close to that normally seen in humans. Of note, because of the equivalency in protein expression and reduced HDL between heterozygotes and homozygotes, the Ldlr^h/+ genotype has been more extensively characterized.

The dominant type 1 diabetes mutation Akita (Ins2^C96Y) has a C96Y amino acid substitution in the insulin II gene; this results in improper folding of pro-insulin in the endoplasmic reticulum and causes eventual pancreatic islet beta-cell death. As a consequence, heterozygous (Ins2^C96Y/+) males develop insulin dependent diabetes around one month of age, including hyperglycemia, hypoinsulinemia, polydipsia and polyuria, without obesity or insulitis. Heterozygous males are more severely affected than females.

Stock No. 012307: Mice homozygous for human APOE*4 and heterozygous for human LDLR (Apoe^4/4 Ldlr^h/+) are called E4h mice. E4h mice are viable and fertile with low plasma cholesterol (normal non-HDL cholesterol) presumably due to increased Ldlr metabolism in the liver. E4h mice are highly sensitive to diet-induced dyslipidemia. Specifically, when maintained on high fat/cholesterol diet mirroring that consumed by humans, E4h animals develop hypercholesterolemia and atherosclerosis. The donating investigator reports mice homozygous for Apoe⁴ and homozygous for Ldlr^h are viable and fertile with no breeding problems.

Stock No. 012628: Mice homozygous for human APOE*4, heterozygous for human LDLR and heterozygous for Akita (Apoe^4/4 Ldlr^h/+ Ins2^C96Y/+) are called E4hAkita mice. E4hAkita mice are viable and fertile. The phenotype of E4hAkita males is described below. E4hAkita males develop spontaneous diabetes (by two months of age) and atherosclerosis. In addition, males are hyperphagic (but have reduced body weight) and hypoinsulinemic, with a modest but significant reduction of plasma triglycerides. Combining the Ldlr^h-induced elevation in non-HDL/HDL cholesterol ratio with the diabetes (Akita)-induced increase in small, cholesterol-enriched, apoB48-containing VLDL results in E4hAkita mice having a non-HDL/HDL cholesterol ratio (~3) that is increased ~6-fold compared to wildtype mice and very close to the human ratio (~3). E4hAkita mice exhibit distinct atherosclerotic foam cell lesions in aortic roots, despite having plasma total cholesterol within the normal physiological range (<120 mg/dl) observed for wildtype mice. Of note, no atherosclerosis is reported for apoE4 homozygotes alone (E4 mice), with hLDLR (E4h mice) or with diabetes (E4Akita mice).