Researchers have developed a groundbreaking approach to tackling obesity by targeting fat absorption in the small intestine.
Researchers have introduced an innovative method to combat obesity by focusing on fat absorption in the small intestine. This advanced nanoparticle system, designed to deliver therapeutic molecules directly to the digestive tract, has demonstrated considerable promise in preventing obesity caused by diet.
Presented at UEG Week 2024, the study focuses on an enzyme called Sterol O-acyltransferase 2 (SOAT2), which plays a critical role in fat absorption in the small intestine.[1,2] By inhibiting this enzyme in the small intestine, the study offers a promising therapeutic approach to reduce fat absorption and potentially prevent obesity.
Despite extensive research into fat metabolism, effective inhibitors of intestinal fatty acid uptake have until now remained elusive. “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. “While most strategies focus on reducing dietary fat intake, our approach targets the body’s fat absorption process directly.”
Nanoparticle-Based Delivery System
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,” said Dr. 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.”
Mechanism of SOAT2 Inhibition
The study also uncovered the underlying mechanism by which SOAT2 regulates fat absorption. Inhibition of SOAT2 in the small intestine triggers the 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,[3,4] whereas this intestine-specific approach circumvents that risk, offering a safer and more focused treatment for obesity.
Professor Zhaoyan Jiang, the study supervisor, explained, “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 buildup there – a risk our treatment avoids by focusing only on intestinal SOAT2.”
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.
“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”, Professor Jiang concluded.
- Azuma, Y., Kawasaki, T., Ikemoto, K., Obata, K., Ohno, N., Sajiki, N., Yamada, T., Yamasaki, M., & Nobuhara, Y. (1998). A study on the effects of dietary fatty acids. Japanese Journal of Pharmacology, 78, 355-364.
- Marzetta, C. A., Savoy, Y. E., Freeman, A. M., Long, C. A., Pettini, J. L., Hagar, R. E., Inskeep, P. B., Davis, K., Stucchi, A. F., & Nicolosi, R. J. (1994). Sterol O-acyltransferase activity in the esterification of cholesterol. Journal of Lipid Research, 35, 1829-1838.
- Alger, H. M., Brown, J. M., Sawyer, J. K., Kelley, K. L., Shah, R., Wilson, M. D., Willingham, M. C., & Rudel, L. L. (2010). The role of SOAT2 in cholesterol esterification in the liver. Journal of Biological Chemistry, 285(19), 14267-14277.
- Brown, J. M., Bell, T. A. III, Alger, H. M., Sawyer, J. K., Smith, T. L., Kelley, K., Shah, R., Wilson, M. D., Davis, M. A., Lee, R. G., Graham, M. J., Crooke, R. M., & Rudel, L. L. (2008). SOAT2 inhibition in hepatic cholesterol metabolism. Journal of Biological Chemistry, 283(15), 10522-10532.
Reference: “siRNA/CS-PLGA Nanoparticle System Targeting Knockdown Intestinal SOAT2 Reduced Intestinal Lipid Uptake and Alleviated Obesity” by Jingjia Liang, Wentao Shao, Pu Ni, Qian Liu, Weirui Kong, Weiyi Shen, Qihan Wang, Anhua Huang, Guixin Zhang, Yulong Yang, Hongliang Xin, Zhaoyan Jiang and Aihua Gu, 19 September 2024, Advanced Science.
DOI: 10.1002/advs.202403442
Meeting: UEG Week 2024