Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia

Hirotaka Fukami; Jun Morinaga; Hironori Nakagami; Hiroki Hayashi; Yusuke Okadome; Eiji Matsunaga; Tsuyoshi Kadomatsu; Haruki Horiguchi; Michio Sato; Taichi Sugizaki; Takashige Kuwabara; Keishi Miyata; Masashi Mukoyama; Ryuichi Morishita; Yuichi Oike

doi:10.1016/j.xcrm.2021.100446

Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia

Cell Rep Med. 2021 Nov 16;2(11):100446. doi: 10.1016/j.xcrm.2021.100446.

Authors

Hirotaka Fukami^{1

2

3}, Jun Morinaga^{1

2

3}, Hironori Nakagami⁴, Hiroki Hayashi⁴, Yusuke Okadome¹, Eiji Matsunaga^{1

2}, Tsuyoshi Kadomatsu^{1

3}, Haruki Horiguchi^{1

3

5}, Michio Sato^{1

3}, Taichi Sugizaki^{1

3}, Takashige Kuwabara², Keishi Miyata^{1

3}, Masashi Mukoyama², Ryuichi Morishita⁶, Yuichi Oike^{1

3

5}

Affiliations

¹ Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-0556, Japan.
² Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-0556, Japan.
³ Center for Metabolic Regulation of Healthy Aging (CMHA), Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-0556, Japan.
⁴ Department of Health Development and Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
⁵ Department of Aging and Geriatric Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-0556, Japan.
⁶ Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.

Abstract

Dyslipidemia is a risk factor for cardiovascular disease (CVD), a major cause of death worldwide. Angiopoietin-like protein 3 (ANGPTL3), recognized as a new therapeutic target for dyslipidemia, regulates the metabolism of low-density lipoprotein-cholesterol (LDL-C) and triglycerides. Here, we design 3 epitopes (E1-E3) for use in development of a peptide vaccine targeting ANGPTL3 and estimate effects of each on obesity-associated dyslipidemia in B6.Cg-Lep^ob /J (ob/ob) mice. Vaccination with the E3 (³²EPKSRFAMLD⁴¹) peptide significantly reduces circulating levels of triglycerides, LDL-C, and small dense (sd)-LDL-C in ob/ob mice and decreases obese-induced fatty liver. Moreover, E3 vaccination does not induce cytotoxicity in ob/ob mice. Interestingly, the effect of E3 vaccination on dyslipidemia attenuates development of atherosclerosis in B6.KOR/StmSlc-Apoe^shl mice fed a high-cholesterol diet, which represent a model of severe familial hypercholesterolemia (FH) caused by ApoE loss of function. Taken together, ANGPTL3 vaccination could be an effective therapeutic strategy against dyslipidemia and associated diseases.

Keywords: ANGPTL3; LDL cholesterol; atherosclerosis; dyslipidemia; fatty liver; peptide vaccine; small dense LDL cholesterol; triglyceride.

Publication types

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

MeSH terms

Angiopoietin-Like Protein 3 / metabolism*
Angiopoietin-Like Protein 8 / metabolism
Animals
Antigens / immunology
Atherosclerosis / complications
Autoimmunity
Cell Death
Disease Models, Animal
Dyslipidemias / blood
Dyslipidemias / complications
Dyslipidemias / immunology*
Hyperlipoproteinemia Type II / blood
Hyperlipoproteinemia Type II / complications
Hyperlipoproteinemia Type II / immunology*
Lipid Metabolism
Liver / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Obesity / blood
Obesity / complications
Obesity / immunology*
Triglycerides / blood
Vaccination
Vaccines / immunology*

Substances

ANGPTL8 protein, mouse
Angiopoietin-Like Protein 3
Angiopoietin-Like Protein 8
Antigens
Triglycerides
Vaccines