2. Academic Validation
  3. siRNA/CS-PLGA Nanoparticle System Targeting Knockdown Intestinal SOAT2 Reduced Intestinal Lipid Uptake and Alleviated Obesity

siRNA/CS-PLGA Nanoparticle System Targeting Knockdown Intestinal SOAT2 Reduced Intestinal Lipid Uptake and Alleviated Obesity

  • Adv Sci (Weinh). 2024 Oct;11(40):e2403442. doi: 10.1002/advs.202403442.
Jingjia Liang 1 2 3,  Wentao Shao 4 5,  Pu Ni 1 2 3,  Qian Liu 1 2 3,  Weirui Kong 1 2 3,  Weiyi Shen 4,  Qihan Wang 4,  Anhua Huang 4,  Guixin Zhang 6,  Yulong Yang 4,  Hongliang Xin 7,  Zhaoyan Jiang 4,  Aihua Gu 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Reproductive Medicne and Offspring Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
  • 2 Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, Nanjing Medical University, Nanjing, 211166, China.
  • 3 Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Center for Global Health, Nanjing Medical University, Nanjing, 211166, China.
  • 4 Center of Gallstone Disease, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 201200, China.
  • 5 School of Instrument Science and Engineering, Southeast University, Nanjing, 210096, China.
  • 6 General Surgery Department, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116027, China.
  • 7 Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
PMID: 39297413 DOI: 10.1002/advs.202403442
Abstract

Effective inhibition of intestinal lipid uptake is an efficient strategy for the treatment of disorders related to lipid metabolism. Sterol O-acyltransferase 2 (SOAT2) is responsible for the esterification of free Cholesterol and fatty acids into cholesteryl esters. We found that intestine-specific SOAT2 knockout (Soat2I-KO) mice was capable to prevent the development of dietary induced obesity due to reduced intestinal lipid absorption. Soat2 siRNA/CS-PLGA nanoparticle system was constructed to enable intestinal delivery and inhibition of Soat2. This nanoparticle system was composed of PLGA-block-PEG and chitosan specifically delivering Soat2 siRNAs into small intestines in mice, effectively inhibit intestinal lipid uptake and resolving obesity. In revealing the underlying mechanism by which intestinal SOAT2 regulating fatty acid uptake, enhanced CD36 ubiquitination degradation was found in enterocytes upon SOAT2 inhibition. Insufficient free Cholesterol esterification promoted endoplasmic reticulum stress and recruitment of E3 Ligase RNF5 to activate CD36 ubiquitination in SOAT2 knockdown enterocytes. This work demonstrates a potential modulatory function of intestinal SOAT2 on lipid uptake highlighting the therapeutic effect on obesity by targeting intestinal SOAT2, exhibiting promising translational relevance in the siRNA therapeutic-based treatment for obesity.

Keywords

CD36; PLGA‐b‐PEG; Sterol O‐acyltransferase 2; intestinal fatty acid absorption; obesity.

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