A new mouse mutant for the LDL receptor identified using ENU mutagenesis

Karen L Svenson,Nadav Ahituv,Rebecca S Durgin,Holly Savage,Phyllis A Magnani,Oded Foreman,Beverly Paigen,Luanne L Peters

doi:10.1194/jlr.m800303-jlr200

Karen L Svenson, Nadav Ahituv + Show 6 more

Open Access

https://doi.org/10.1194/jlr.m800303-jlr200

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Abstract

In an effort to discover new mouse models of cardiovascular disease using N-ethyl-N-nitrosourea (ENU) mutagenesis followed by high-throughput phenotyping, we have identified a new mouse mutation, C699Y, in the LDL receptor (Ldlr), named wicked high cholesterol (WHC). When WHC was compared with the widely used Ldlr knockout (KO) mouse, notable phenotypic differences between strains were observed, such as accelerated atherosclerotic lesion formation and reduced hepatosteatosis in the ENU mutant after a short exposure to an atherogenic diet. This loss-of-function mouse model carries a single base mutation in the Ldlr gene on an otherwise pure C57BL/6J (B6) genetic background, making it a useful new tool for understanding the pathophysiology of atherosclerosis and for evaluating additional genetic modifiers regulating hyperlipidemia and atherogenesis. Further investigation of genomic differences between the ENU mutant and KO strains may reveal previously unappreciated sequence functionality.

Highlights

In an effort to discover new mouse models of cardiovascular disease using N-ethyl-N-nitrosourea (ENU) mutagenesis followed by high-throughput phenotyping, we have identified a new mouse mutation, C699Y, in the LDL receptor (Ldlr), named wicked high cholesterol (WHC)
Mice were generated as part of a large-scale mutagenesis effort using high-throughput phenotyping to identify new mouse models of complex heart, Abbreviations: Apolipoprotein E (Apoe), apolipoprotein E; ATH, atherogenic; ENU, N-ethyl-N-nitrosourea; FH, familial hypercholesterolemia; G3, threegeneration; KO, knockout; Ldlr, LDL receptor; WHC, wicked high cholesterol
For assessment of atherosclerotic lesion development, female and male wicked high cholesterol (WHC) mice were provided with three different diets: the standard chow diet; a Western diet containing 21% fat, 34% sucrose, 0.15% cholesterol, and no cholic acid; and the ATH diet described above

Summary

METHODS

Mice were generated as part of a large-scale mutagenesis effort using high-throughput phenotyping to identify new mouse models of complex heart, Abbreviations: Apoe, apolipoprotein E; ATH, atherogenic; ENU, N-ethyl-N-nitrosourea; FH, familial hypercholesterolemia; G3, threegeneration; KO, knockout; Ldlr, LDL receptor; WHC, wicked high cholesterol

Present address

F controls G3 35363 F G3 35364 F G3 35367 F G3 32776 F

RESULTS

C W ATH C W ATH