Acta Pharmaceutica Sinica B (Dec 2024)
Intestinal epithelial cell NCoR deficiency ameliorates obesity and metabolic syndrome
- Shaocong Hou,
- Hengcai Yu,
- Caihong Liu,
- Andrew M.F. Johnson,
- Xingfeng Liu,
- Qian Jiang,
- Qijin Zhao,
- Lijuan Kong,
- Yanjun Wan,
- Xiaowei Xing,
- Yibing Chen,
- Jingwen Chen,
- Qing Wu,
- Peng Zhang,
- Changtao Jiang,
- Bing Cui,
- Pingping Li
Affiliations
- Shaocong Hou
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100730, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China
- Hengcai Yu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100730, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China
- Caihong Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100730, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China
- Andrew M.F. Johnson
- The Access to Advanced Health Institute, Seattle, Washington 98102, USA
- Xingfeng Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100730, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China
- Qian Jiang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100730, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China
- Qijin Zhao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100730, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China
- Lijuan Kong
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100730, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China
- Yanjun Wan
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100730, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China
- Xiaowei Xing
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100730, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China
- Yibing Chen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100730, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China
- Jingwen Chen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100730, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China
- Qing Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China
- Peng Zhang
- Division of Metabolic and Bariatric Surgery, Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing 100050, China; Corresponding authors.
- Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; Corresponding authors.
- Bing Cui
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China; Corresponding authors.
- Pingping Li
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Diabetes Research Center of Chinese Academy of Medical Sciences, Beijing 100730, China; CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing 100050, China; Corresponding authors.
- Journal volume & issue
-
Vol. 14,
no. 12
pp. 5267 – 5285
Abstract
Nuclear receptor corepressor (NCoR1) interacts with various nuclear receptors and regulates the anabolism and catabolism of lipids. An imbalance in lipid/energy homeostasis is also an important factor in obesity and metabolic syndrome development. In this study, we found that the deletion of NCoR1 in intestinal epithelial cells (IECs) mainly activated the nuclear receptor PPARα and attenuated metabolic syndrome by stimulating thermogenesis. The increase in brown adipose tissue thermogenesis was mediated by gut-derived tricarboxylic acid cycle intermediate succinate, whose production was significantly enhanced by PPARα activation in the fed state. Additionally, NCoR1 deletion derepressed intestinal LXR, increased cholesterol excretion, and impaired duodenal lipid absorption by decreasing bile acid hydrophobicity, thereby reversing the possible negative effects of intestinal PPARα activation. Therefore, the simultaneous regulatory effect of intestinal NCoR1 on both lipid intake and energy expenditure strongly suggests that it is a promising target for developing metabolic syndrome treatment.
