A vaccine targeted at CETP alleviates high fat and high cholesterol diet-induced atherosclerosis and non-alcoholic steatohepatitis in rabbit

Yi-Wei Liaw; Chi-Yu Lin; Yu-Sheng Lai; Tzu-Chung Yang; Chau-Jong Wang; Jacqueline Whang-Peng; Leroy F Liu; Chia-Po Lin; Shin Nieh; Shao-Chun Lu; Jaulang Hwang

doi:10.1371/journal.pone.0111529

A vaccine targeted at CETP alleviates high fat and high cholesterol diet-induced atherosclerosis and non-alcoholic steatohepatitis in rabbit

PLoS One. 2014 Dec 8;9(12):e111529. doi: 10.1371/journal.pone.0111529. eCollection 2014.

Authors

Affiliations

¹ Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan; Department of Biochemistry, Medical College, Taipei Medical University, Taipei, Taiwan.
² Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; Department of Biochemistry, Medical College, Taipei Medical University, Taipei, Taiwan.
³ Department of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁴ Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan.
⁵ Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
⁶ Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan; Department of Pharmacology, The University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America.
⁷ Division of Drug Biology, Bureau of Food and Drug Analysis, Department of Health, Executive Yuan, Taiwan.
⁸ Department of Pathology, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan.

Abstract

Low HDL-C levels are associated with atherosclerosis and non-alcoholic steatohepatitis, and increased levels may reduce the risk of these diseases. Inhibition of cholesteryl ester transfer protein (CETP) activity is considered a promising strategy for increasing HDL-C levels. Since CETP is a self-antigen with low immunogenicity, we developed a novel CETP vaccine (Fc-CETP6) to overcome the low immunogenicity of CETP and for long-term inhibition of CETP activity. The vaccine consists of a rabbit IgG Fc domain for antigen delivery to antigen-presenting cells fused to a linear array of 6 repeats of a CETP epitope to efficiently activate B cells. Rabbits were fed a high fat/cholesterol (HFC) diet to induce atherosclerosis and NASH, and immunized with Fc-CETP6 vaccine. The Fc-CETP6 vaccine successfully elicited anti-CETP antibodies and lowered plasma CETP activity. The levels of plasma HDL-C and ApoA-I were higher, and plasma ox-LDL lower, in the Fc-CETP6-immunized rabbits as compared to the unimmunized HFC diet-fed rabbits. Pathological analyses revealed less lipid accumulation and inflammation in the aorta and liver of the Fc-CETP6-immunized rabbits. These results show that the Fc-CETP6 vaccine efficiently elicited antibodies against CETP and reduced susceptibility to both atherosclerosis and steatohepatitis induced by the HFC diet. Our findings suggest that the Fc-CETP6 vaccine may improve atherosclerosis and NASH and has high potential for clinical use.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies / blood
Antibodies / immunology
Apolipoprotein A-I / metabolism
Atherosclerosis / etiology*
Atherosclerosis / pathology
Atherosclerosis / prevention & control*
Cholesterol / blood
Cholesterol / metabolism
Cholesterol Ester Transfer Proteins / genetics
Cholesterol Ester Transfer Proteins / immunology*
Cholesterol Ester Transfer Proteins / metabolism
Diet, High-Fat / adverse effects*
Disease Models, Animal
Female
Fibrosis
Gene Expression
Humans
Immunoglobulin Fc Fragments / genetics
Immunoglobulin Fc Fragments / immunology
Lipoproteins, LDL / metabolism
Non-alcoholic Fatty Liver Disease / etiology*
Non-alcoholic Fatty Liver Disease / pathology
Non-alcoholic Fatty Liver Disease / prevention & control*
Rabbits
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / immunology
Vaccines / genetics
Vaccines / immunology*

Substances

Antibodies
Apolipoprotein A-I
Cholesterol Ester Transfer Proteins
Immunoglobulin Fc Fragments
Lipoproteins, LDL
Recombinant Fusion Proteins
Vaccines
oxidized low density lipoprotein
Cholesterol

Grants and funding

This study was supported by research grants NHRI-EX101-10153SI (http://goo.gl/bx7Wul) and NHRI-EX102-10153SI (http://goo.gl/w3824A) from the National Health Research Institutes of Taiwan. Dr. Shao-Chun Lu and Dr. Jaulang Hwang received the funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.