Apolipoprotein CIII (apoCIII) is increased in obesity-induced insulin resistance and type-2 diabetes. Emerging evidences support the advantages of small interfering RNAs (siRNAs) to target disease-causing genes. The aim of this study was to develop siRNAs for in vivo silencing of apoCIII and investigate if this results in metabolic improvements comparable to what we have seen using antisense oligonucelotides against apoCIII. Twenty-four siRNAs were synthesized and tested in a dual luciferase reporter assay. The eight best were selected, based on knockdown at 20 nM, and of these, two were selected based on IC50 values. In vivo experiments were performed in ob/ob mice, an obese animal model for diabetes. To determine the dose-dependency, efficacy, duration of effect and therapeutic dose we used a short protocol giving the apoCIII-siRNA mix for three days. To evaluate long-term metabolic effects mice were treated for three days, every second week for eight weeks. The siRNA mix effectively and selectively reduced expression of apoCIII in liver in vivo. Treatment had to be repeated every two weeks to maintain a suppression of apoCIII. The reduction of apoCIII resulted in increased LPL activity, lower triglycerides, reduced liver fat, ceased weight gain, enhanced insulin sensitivity, and improved glucose homeostasis. No off-target or side effects were observed during the eight-week treatment period. These results suggest that in vivo silencing of apoCIII with siRNA, is a promising approach with the potential to be used in the battle against obesity-induced metabolic disorders.
|Number of pages||20|
|Early online date||30 Aug 2022|
|Publication status||Published online - 30 Aug 2022|
Bibliographical noteFunding Information:
AstraZeneca; Diabetes and Wellness Foundation; European Research Council, Grant/Award Number: ERC‐2018‐AdG 834860 EYELETS; Funds of Karolinska Institutet; Jonas & Christina af Jochnick Foundation; Novo Nordisk Fonden; Skandia Insurance Company Ltd.; Strategic Research Program in Diabetes at Karolinska Institutet; Svenska Diabetesstiftelsen; Swedish Diabetes Association; The Bert von Kantzow Foundation; The Family Erling‐Persson Foundation; The Family Knut and Alice Wallenberg Foundation; The Sigurd and Elsa Goljes Foundation; The Swedish Association for Diabetology; The Swedish Research Council Funding information
We thank Kristina Edvardsson, for technical support. This work was supported by the Swedish Diabetes Association, Funds of Karolinska Institutet, The Sigurd and Elsa Goljes Foundation, The Swedish Research Council, Novo Nordisk Foundation, The Family Erling‐Persson Foundation, Strategic Research Program in Diabetes at Karolinska Institutet, The Family Knut and Alice Wallenberg Foundation, The Stichting af Jochnick Foundation, Skandia Insurance Company, Ltd., Diabetes and Wellness Foundation, The Bert von Kantzow Foundation, Svenska Diabetesstiftelsen, AstraZeneca, Swedish Association for Diabetology and The ERC‐EYLETS 834860.
© 2022 International Union of Biochemistry and Molecular Biology.
- apolipoprotein CIII
- glucose homeostasis
- insulin sensitivity
- metabolic syndrome