Adopting a high-fat diet leads to an increased risk for obesity, type 2 diabetes, cardiovascular disease and fatty liver. A study in mice from the Karolinska Institutet in Sweden shows that it is possible to eliminate the harmful effects of a high-fat diet by reducing apolipoprotein CIII (apoCIII) levels, a major regulator of lipid metabolism. The study is published in the journal Advances in science.
Increased levels of the protein apoCIII are associated with cardiovascular disease, insulin resistance and type 2 diabetes. Researchers at the Rolf Luft Research Center, Karolinska Institutet, have previously shown that an increase in apoCIII in the hormone-releasing part of the pancreas, the small islets of Langerhans, in parallel with the development of insulin resistance and diabetes.
The same researchers have now studied two groups of mice that received a high-fat diet from the age of 8 weeks, and a control group of mice on a normal diet. One of the groups on a high-fat diet received a so-called antisense treatment (ASO) after 10 weeks on the diet to reduce apoCIII levels, and the other group had been treated with ASO from the beginning and thus ‘prevents an increase in apoCIII.
“After a period of 10 weeks, all mice in the first group were obese, insulin resistant and had liver steatosis. However, after ASO treatment, still on the high-fat diet, glucose metabolism was reduced. normalization, weight and morphology of the liver, “said Ismael Valladolid-Acebes, assistant professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet, and first author of the study.
In the group treated with ASO directly from the outset, the development of metabolic changes was inhibited, and the animals had the same body production and metabolism as the normal diet-controlled mice. The mechanisms underlying the effect of apoCIII-depleting treatment include increased lipase enzyme activity and uptake of lipids by mediators to the liver. Fatty acids were transferred by fatty acid oxidation to the biochemical process in the liver called the ketogenic pathway and then converted to ketones used for heat generation in adipose tissue.
“Thus, we could show that a reduction in apoCIII levels, despite the inclusion of a high-fat diet, not only protects against, but also restores the -destructive metabolic changes caused by fat by stimulating increased insulin sensitivity, “says Lisa Juntti-Berggren, professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet, and lead author of the study.
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The research was supported by the Swedish Diabetes Association, Karolinska Institutet Foundations and Funds, Swedish Research Council, Novo Nordisk Foundation, The Family Erling-Persson Foundation, Karolinska Institutet’s Strategic Research Program in Diabetes, The Knut and Alice Wallenberg Foundation, The Stichting af Jochnick Foundation, Skandia Insurance Company Ltd., the Diabetes and Wellness Foundation, The Bert von Kantzow Foundation, Svenska Diabetesstiftelsen, AstraZeneca, Swedish Association for Diabetology and the European Research Council (ERC).
Co-author Per-Olof Berggren is the co-founder and CEO of Biocrine, a biotechnology company that targets apoCIII as a potential target drug for diabetes. Lisa Juntti-Berggren is a consultant for the same company and has participated in advisory boards for NovoNordisk, AstraZeneca and Sanofi.
Disclosure: “Decreased apolipoprotein CIII protects against metabolic changes induced by a high diet”. Ismael Valladolid-Acebes, Karin Åvall, Patricia Recio-López, Noah Moruzzi, Galyna Bryzgalova, Marie Björnholm, Anna Krook, Elena Fauste Alonso, Madelene Ericsson, Fredrik Landfors, Stefan K Nilsson, Per-Olof Juntti, Berggren Berrengren Advances in science, online 12 March 2021, doi: 10.1126 / sciadv.abc2931.
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