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ANGPTL4 silencing v...
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Deng, MingjuanNutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, Netherlands
(författare)
ANGPTL4 silencing via antisense oligonucleotides reduces plasma triglycerides and glucose in mice without causing lymphadenopathy
- Artikel/kapitelEngelska2022
Förlag, utgivningsår, omfång ...
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American Society for Biochemistry and Molecular Biology,2022
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electronicrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:umu-198495
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https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-198495URI
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https://doi.org/10.1016/j.jlr.2022.100237DOI
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Språk:engelska
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Sammanfattning på:engelska
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Angiopoietin-like 4 (ANGPTL4) is an important regulator of plasma triglyceride (TG) levels and an attractive pharmacological target for lowering plasma lipids and reducing cardiovascular risk. Here, we aimed to study the efficacy and safety of silencing ANGPTL4 in the livers of mice using hepatocyte-targeting GalNAc-conjugated antisense oligonucleotides (ASOs). Compared with injections with negative control ASO, four injections of two different doses of ANGPTL4 ASO over 2 weeks markedly downregulated ANGPTL4 levels in liver and adipose tissue, which was associated with significantly higher adipose LPL activity and lower plasma TGs in fed and fasted mice, as well as lower plasma glucose levels in fed mice. In separate experiments, injection of two different doses of ANGPTL4 ASO over 20 weeks of high-fat feeding reduced hepatic and adipose ANGPTL4 levels but did not trigger mesenteric lymphadenopathy, an acute phase response, chylous ascites, or any other pathological phenotypes. Compared with mice injected with negative control ASO, mice injected with ANGPTL4 ASO showed reduced food intake, reduced weight gain, and improved glucose tolerance. In addition, they exhibited lower plasma TGs, total cholesterol, LDL-C, glucose, serum amyloid A, and liver TG levels. By contrast, no significant difference in plasma alanine aminotransferase activity was observed. Overall, these data suggest that ASOs targeting ANGPTL4 effectively reduce plasma TG levels in mice without raising major safety concerns.
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Biuppslag (personer, institutioner, konferenser, titlar ...)
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Kutrolli, EldaLipigon Pharmaceuticals AB, Umeå, Sweden
(författare)
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Sadewasser, AnneSecarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany
(författare)
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Michel, SvenSecarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany
(författare)
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Joibari, Masoumeh MotamediLipigon Pharmaceuticals AB, Umeå, Sweden
(författare)
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Jaschinski, FrankSecarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany
(författare)
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Olivecrona, GunillaUmeå universitet,Fysiologisk kemi,Lipigon Pharmaceuticals AB, Umeå, Sweden(Swepub:umu)guol0002
(författare)
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Nilsson, Stefan K.Lipigon Pharmaceuticals AB, Umeå, Sweden
(författare)
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Kersten, SanderNutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, Netherlands
(författare)
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Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, NetherlandsLipigon Pharmaceuticals AB, Umeå, Sweden
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Journal of Lipid Research: American Society for Biochemistry and Molecular Biology63:70022-22751539-7262
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