Dataset Information

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

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.

SUBMITTER: Fukami H

PROVIDER: S-EPMC8606905 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Fukami Hirotaka H Morinaga Jun J Nakagami Hironori H Hayashi Hiroki H Okadome Yusuke Y Matsunaga Eiji E Kadomatsu Tsuyoshi T Horiguchi Haruki H Sato Michio M Sugizaki Taichi T Kuwabara Takashige T Miyata Keishi K Mukoyama Masashi M Morishita Ryuichi R Oike Yuichi Y

Cell reports. Medicine 20211116 11

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-Lepob /J (ob/ob</ ...[more]

PMID: 34841293

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Project description:Familial hypercholesterolemia (FH) is a lipoprotein disorder characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and an increased risk of premature atherosclerotic cardiovascular disease. Recent evidences have shown that several glycerophospholipid species were markedly altered in experimental FH animals and exhibited diverse bioactivities. Nevertheless, the glycerophospholipid profiles and their associated biological implications in human FH remain largely unknown. In this study, we sought to comprehensively delineate the glycerophospholipid phenotypes in human FH and to investigate the functional roles of key FH-altered glycerophospholipid molecules on cholesterol metabolism. Targeted analysis of 328 glycerophospholipid metabolites was used to profile the differentiated alterations in patients with homozygous FH (HoFH; n = 181), heterozygous FH (HeFH; n = 452), and non-FH hypercholesterolemia (n = 382). Our findings revealed that the glycerophospholipid phenotypes of FH and non-FH hypercholesterolemia were dominated by a spectrum of metabolites involved in the lysophosphatidic acid (LPA) metabolism. Among the LPA features, palmitoyl-LPA (16:0) showed significant association with the clinical levels of LDL-C and total cholesterol in HoFH and HeFH populations. Using functional metabolomic strategy and murine FH model, we demonstrated that supplementation with LPA 16:0 elevated the plasma levels of LDL and free/esterified cholesterol and exacerbated the atherosclerotic lesions. Conversely, inhibition of autotaxin-mediated LPA 16:0 production significantly ameliorated dyslipidemia. Mechanistically, we uncovered that LPA 16:0 could disrupt hepatic cholesterol homeostasis by impairing cholesterol excretion and inhibiting primary bile acid synthesis. In summary, our study offers novel insights into lipid metabolism in human FH and posits that targeting LPA metabolism may represent a promising therapeutic strategy for reducing cholesterol levels in the FH population.

Project description:RationaleLow density cholesterol receptor (LDLR) in the liver is critical for the clearance of low-density lipoprotein cholesterol (LDL-C) in the blood. In atherogenic conditions, proprotein convertase subtilisin/kexin 9 (PCSK9) secreted by the liver, in a nonenzymatic fashion, binds to LDLR on the surface of hepatocytes, preventing its recycling and enhancing its degradation in lysosomes, resulting in reduced LDL-C clearance. Our recent studies demonstrate that epsins, a family of ubiquitin-binding endocytic adaptors, are critical regulators of atherogenicity. Given the fundamental contribution of circulating LDL-C to atherosclerosis, we hypothesize that liver epsins promote atherosclerosis by controlling LDLR endocytosis and degradation.ObjectiveWe will determine the role of liver epsins in promoting PCSK9-mediated LDLR degradation and hindering LDL-C clearance to propel atherosclerosis.Methods and resultsWe generated double knockout mice in which both paralogs of epsins, namely, epsin-1 and epsin-2, are specifically deleted in the liver (Liver-DKO) on an ApoE -/- background. We discovered that western diet (WD)-induced atherogenesis was greatly inhibited, along with diminished blood cholesterol and triglyceride levels. Mechanistically, using scRNA-seq analysis on cells isolated from the livers of ApoE-/- and ApoE-/- /Liver-DKO mice on WD, we found lipogenic Alb hi hepatocytes to glycogenic HNF4α hi hepatocytes transition in ApoE-/- /Liver-DKO. Subsequently, gene ontology analysis of hepatocyte-derived data revealed elevated pathways involved in LDL particle clearance and very-low-density lipoprotein (VLDL) particle clearance under WD treatment in ApoE-/- /Liver-DKO, which was coupled with diminished plasma LDL-C levels. Further analysis using the MEBOCOST algorithm revealed enhanced communication score between LDLR and cholesterol, suggesting elevated LDL-C clearance in the ApoE-/- Liver-DKO mice. In addition, we showed that loss of epsins in the liver upregulates of LDLR protein level. We further showed that epsins bind LDLR via the ubiquitin-interacting motif (UIM), and PCSK9-triggered LDLR degradation was abolished by depletion of epsins, preventing atheroma progression. Finally, our therapeutic strategy, which involved targeting liver epsins with nanoparticle-encapsulated siRNAs, was highly efficacious at inhibiting dyslipidemia and impeding atherosclerosis.ConclusionsLiver epsins promote atherogenesis by mediating PCSK9-triggered degradation of LDLR, thus raising the circulating LDL-C levels. Targeting epsins in the liver may serve as a novel therapeutic strategy to treat atherosclerosis by suppression of PCSK9-mediated LDLR degradation.

Dataset Information

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

Publications

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

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