A cutting-edge nanoparticle system, engineered to deliver therapeutic molecules directly to the digestive tract, has shown significant potential to prevent diet-induced obesity, according to researchers from the Center of Gallstone Disease, Shanghai East Hospital, Tongji University, China.
The study, ‘Sirna/CS-PLGA nanoparticles system targeting knockout of intestinal SOA SOAT2 reduced intestinal lipid uptake and alleviate obesity’, presented at United European Gastroenterology Week 2024, in Vienna, Austria, the study focuses on an enzyme called Sterol O-acyltransferase 2 (SOAT2), which plays a critical role in fat absorption in the small intestine. By inhibiting this enzyme in the small intestine, the study offers a promising therapeutic approach to reduce fat absorption and potentially prevent obesity.
“For years, researchers have studied fat metabolism, but finding an effective way to block fat absorption has been difficult,” explained lead researcher, Dr Wentao Shao, a PhD candidate specialising in basic medical research at the Center of Gallstone Disease. “While most strategies focus on reducing dietary fat intake, our approach targets the body’s fat absorption process directly."
The research team developed an innovative delivery system using nanoparticles – a tiny capsule made from a polymer core, coated in a protective shell. The system was designed to efficiently carry small interfering RNAs (siRNAs) to the small intestine, where they can reduce SOAT2 expression, inhibiting fat absorption. In mouse models, the animals treated with the nanoparticle therapy absorbed less fat and avoided obesity, even on a high-fat diet.
“This oral treatment offers several advantages”, added Shao. “It’s non-invasive, has low toxicity, and it has high potential for better patient compliance compared to current obesity treatments, which are often invasive or difficult to maintain. This makes it a promising alternative.”
The study also uncovered the underlying mechanism by which SOAT2 regulates fat absorption. Inhibition of SOAT2 in the small intestine triggers degradation of CD36, a protein responsible for transporting fat. This process involves both cellular stress and the recruitment of E3 ligase RNF5, an enzyme that enhances CD36 degradation.
Previous studies have shown that blocking hepatic SOAT2 leads to fat accumulation in the liver, whereas this intestine-specific approach circumvents that risk, offering a safer and more focused treatment for obesity.
“One of the most exciting aspects of this therapy is its ability to target fat absorption in the intestines without affecting the liver. This is important because previous studies showed that blocking SOAT2 in the liver can lead to fat build up there – a risk our treatment avoids by focusing only on intestinal SOAT2,” explained Professor Zhaoyan Jiang, the study’s supervisor, from the Center of Gallstone Disease. “We believe that this nanoparticle system represents a breakthrough in obesity management, offering a new solution that tackles both fat metabolism and diet-related weight gain, potentially ushering in a new era of more effective treatments.”
Looking ahead, the research team plans to test the nanoparticle system in larger animal models to confirm its effectiveness and safety for potential use in humans.
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