Preclinical Research
Apolipoprotein E Deficiency Increases Remnant Lipoproteins and Accelerates Progressive Atherosclerosis, But Not Xanthoma Formation, in Gene-Modified Minipigs

https://doi.org/10.1016/j.jacbts.2017.06.004Get rights and content
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Highlights

  • APOE-deficient Yucatan minipigs were created by recombinant adeno-associated virus mediated gene targeting in porcine fibroblasts followed by somatic cell nuclear transfer.

  • APOE−/− minipigs displayed increased plasma cholesterol and accumulation of APOB48-containing chylomicron remnants on low fat-diet, which was significantly accentuated upon feeding a high-fat, high-cholesterol diet.

  • APOE−/− minipigs showed accelerated progressive atherosclerosis but not xanthoma formation indicating that remnant lipoproteinemia does not induce early lesions but is atherogenic in pre-existing atherosclerosis.

Summary

Deficiency of apolipoprotein E (APOE) causes familial dysbetalipoproteinemia in humans resulting in a higher risk of atherosclerotic disease. In mice, APOE deficiency results in a severe atherosclerosis phenotype, but it is unknown to what extent this is unique to mice. In this study, APOE was targeted in Yucatan minipigs. APOE−/− minipigs displayed increased plasma cholesterol and accumulation of apolipoprotein B-48–containing chylomicron remnants on low-fat diet, which was significantly accentuated upon feeding a high-fat, high-cholesterol diet. APOE−/− minipigs displayed accelerated progressive atherosclerosis but not xanthoma formation. This indicates that remnant lipoproteinemia does not induce early lesions but is atherogenic in pre-existing atherosclerosis.

Key Words

apolipoprotein E
atherosclerosis
pig
remnant cholesterol dysbetalipoproteinemia

Abbreviations and Acronyms

APOB
apolipoprotein B
APOE
apolipoprotein E
cDNA
complementary DNA
HFHC
high-fat high-cholesterol
IDL
intermediate-density lipoprotein
LAD
left anterior descending (coronary artery)
LDL
low-density lipoprotein
LDLR
low-density lipoprotein receptor
LF
low-fat
Neo
neomycin
rAAV
recombinant adeno-associated virus
SMC
smooth muscle cell
VLDL
very-low-density lipoprotein

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Supported by grants from The Danish Heart Association, Copenhagen, Denmark, The Novo Nordisk Foundation, Hellerup, Denmark, The Lundbeck Foundation, Copenhagen, Denmark, The Danish Council for Independent Research—Technology and Production Sciences, Copenhagen, Denmark, and Graduate School of Health, Aarhus University, Aarhus, Denmark. The CNIC is supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Aarhus University owns a patent on porcine APOE targeting with Drs. Bentzon, Sørensen, and Bolund listed as inventors (EP 2134847). Drs. Sørensen, Callesen, and Bolund are members of the EU COST Action BM1308 “Sharing advances on large animal models—SALAAM.” Dr. Bolund is the Chief Scientific Officer of PixieGene. Drs. Bentzon and Sørensen contributed equally to this work.

All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.