Consuming a high-fat diet (HFD) is linked with increased risk for obesity and associated metabolic disorders, including type 2 diabetes, cardiovascular diseases, and fatty liver. Studies by researchers at the Karolinska Institutet in Sweden have now shown that the damaging effects of a high-fat diet can be reversed in mice, by treating the animals with an antisense oligonucleotide (ASO) that reduces levels of apolipoprotein CIII (apoCIII), a key regulator of lipid metabolism.

Reporting on their studies in Science Advances, first author Ismael Valladolid-Acebes, PhD, assistant professor at the department of molecular medicine and surgery, Karolinska Institutet, and colleagues, said the studies demonstrated that interfering with the HFD-induced increase in apoCIII in mice prevented the development of obesity and type 2 diabetes mellitus (T2DM), and point to apoCIII as a potential target for metabolic syndrome. “The overall positive effect on the metabolic phenotype of the ASO-treated mice on HFD is caused by an efficient use of fat for fuel instead of storage and a maintained/restored insulin sensitivity, preventing deleterious metabolic consequences,” they wrote in their published paper, which is titled, “Lowering apolipoprotein CIII protects against high-fat diet-induced metabolic derangements.”

Obesity is a severe risk factor for what is termed “metabolic derangements,” including diabetes mellitus and non-alcoholic fatty liver disease (NAFLD). It has also been shown that serum levels of the lipoprotein apoCIII increase as a result of consuming a high-fat diet, the authors explained. Apolipoprotein CIII is produced primarily in the liver, and plays a key role in lipid metabolism, and it is recognized that increased circulating levels of apoCIII are associated with hypertriglyceridemia and cardiovascular diseases (CVDs), the investigators continued. Interestingly, large scale epidemiological studies have shown that apoCIII gene variants that result in increased levels of the apolipoprotein are associated with NAFLD, hepatic insulin resistance, and T2DM. Conversely, loss-of-function mutations in the apoCIII gene are related to protection against cardiovascular diseases.

Researchers at the Rolf Luft Research Center, Karolinska Institutet, previously showed that apoCIII increases in the hormone-secreting part of the pancreas, the islets of Langerhans, in parallel with the development of insulin resistance and diabetes. For their newly reported research, the scientists studied two groups of mice that were fed a high-fat diet from the age of 8 weeks, and a control group of mice that received a normal diet. The first group was fed an HFD for 10 weeks before the ASO therapy was started, and so had already developed increased apoCIII before initiating ASO treatment. The second group received intraperitoneal injections of the apoCIII-targeting antisense oligonucleotide from the onset of being fed a high-fat diet, thereby preventing an increase in apoCIII.

In the group that was treated with ASO directly from start, the development of metabolic derangements was prevented, and the animals had the same body composition and metabolism as the control mice on a normal diet. The animals that had been consuming an HFD for 10 weeks before ASO therapy initiation had started became obese, but showed reductions in apoCIII and metabolic improvement after four weeks of ASO. “After a period of 10 weeks, all of the mice in the first group were obese, insulin resistant, and had liver steatosis,” Valladolid-Acebes noted. “However, after ASO treatment, still being on the high-fat diet, there was a normalization of glucose metabolism, weight, and liver morphology.”

The mechanisms underlying the effects of the apoCIII-lowering treatment involve increased lipase enzyme activity and receptor-mediated uptake of lipids to the liver, the investigators found. Fatty acids were transferred by fatty acid oxidation (FAO) to the biochemical process in the liver called the ketogenic pathway and then converted to ketones that were used for heat production in brown adipose tissue (BAT). “This resulted in no fat accumulation and preserved morphology and function of liver and BAT,” the team wrote.

“We now show that interference with apoCIII during HFD intake activates lipases and improves hepatic clearance and catabolism of lipids from the circulation … as a result of decreased levels of the apolipoprotein, there is a normalization in insulin sensitivity and an increase in FAO and ketogenesis, while DNL [de novo lipogenesis] and gluconeogenesis are inhibited.”

“Thus, we could demonstrate that a lowering of apoCIII levels, despite ongoing intake of a high-fat diet, not only protects against, but also reverses the deleterious fat-induced metabolic derangements by promoting an overall increased insulin sensitivity,” commented Lisa Juntti-Berggren, PhD, professor at the department of molecular medicine and surgery, Karolinska Institutet, and senior author of the study.

The researchers noted that the link between increased levels of apoCIII and NAFLD highlights the clinical relevance of their studies. NAFLD can be considered the hepatic component of the metabolic syndrome, represents a spectrum of liver damage, and is closely associated with obesity, insulin resistance, and T2DM, they explained. “NAFLD affects 40 to 50% of the total population in Europe and the United States, and the prevalence is even higher in risk groups with obesity and T2DM,” they added. “Our findings thus identify apoCIII as a central multifaceted drug target in the metabolic syndrome.”

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