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

Jeong Shim; Christian Bo Poulsen; Mette K Hagensen; Torben Larsen; Peter M H Heegaard; Christina Christoffersen; Lars Bolund; Mette Schmidt; Ying Liu; Juan Li; Rong Li; Henrik Callesen; Jacob F Bentzon; Charlotte B Sørensen

doi:10.1016/j.jacbts.2017.06.004

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

JACC Basic Transl Sci. 2017 Oct 30;2(5):591-600. doi: 10.1016/j.jacbts.2017.06.004. eCollection 2017 Oct.

Authors

Jeong Shim^{1

2}, Christian Bo Poulsen^{1

2}, Mette K Hagensen^{1

2}, Torben Larsen³, Peter M H Heegaard⁴, Christina Christoffersen⁵, Lars Bolund⁶, Mette Schmidt⁷, Ying Liu³, Juan Li³, Rong Li³, Henrik Callesen³, Jacob F Bentzon^{1

2

8}, Charlotte B Sørensen^{1

2}

Affiliations

¹ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
² Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
³ Department of Animal Science, Aarhus University, Aarhus, Denmark.
⁴ National Veterinary Institute, Technical University of Denmark, Lyngby, Denmark.
⁵ Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
⁶ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁷ Section for Veterinary Reproduction and Obstetrics, Department of Veterinary Clinical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸ Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.

Abstract

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.

Keywords: APOB, apolipoprotein B; APOE, apolipoprotein E; 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; SMC, smooth muscle cell; VLDL, very-low-density lipoprotein; apolipoprotein E; atherosclerosis; cDNA, complementary DNA; pig; rAAV, recombinant adeno-associated virus; remnant cholesterol dysbetalipoproteinemia.