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ANGPTL4 silencing v...
ANGPTL4 silencing via antisense oligonucleotides reduces plasma triglycerides and glucose in mice without causing lymphadenopathy
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- Deng, Mingjuan (författare)
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, Netherlands
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- Kutrolli, Elda (författare)
- Lipigon Pharmaceuticals AB, Umeå, Sweden
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- Sadewasser, Anne (författare)
- Secarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany
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- Michel, Sven (författare)
- Secarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany
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- Joibari, Masoumeh Motamedi (författare)
- Lipigon Pharmaceuticals AB, Umeå, Sweden
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- Jaschinski, Frank (författare)
- Secarna Pharmaceuticals GmbH & Co. KG, Planegg, Germany
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- Olivecrona, Gunilla (författare)
- Umeå universitet,Fysiologisk kemi,Lipigon Pharmaceuticals AB, Umeå, Sweden
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- Nilsson, Stefan K. (författare)
- Lipigon Pharmaceuticals AB, Umeå, Sweden
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- Kersten, Sander (författare)
- Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, Netherlands
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(creator_code:org_t)
- American Society for Biochemistry and Molecular Biology, 2022
- 2022
- Engelska.
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Ingår i: Journal of Lipid Research. - : American Society for Biochemistry and Molecular Biology. - 0022-2275 .- 1539-7262. ; 63:7
- Relaterad länk:
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Microbiology in the medical area (hsv//eng)
Nyckelord
- adipose tissue
- angiopoietin-like 4
- antisense oligonucleotides
- fasting
- high-fat diet
- lipase/ lipoprotein
- lipoproteins/metabolism
- liver
- triglycerides
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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