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 meta...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 PPARa 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 PPARa 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 PPARa 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.展开更多
基金supported by grants from the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2021-I2M-1-016,2016-I2M-1-011,2016-I2M-3-008 and 2017-I2M-1-008,China)the Special Research Fund for Central Universities,Peking Union Medical College(3332022047,China)+4 种基金the Beijing Outstanding Young Scientist Program(BJJWZYJH01201910023028,China)the National Natural Science Foundation of China(81703588,82473984,81622010,81770800,and 81874316)the CAMS Central Public-interest Scientific Institution Basal Research Fund(2017RC31009 and 2018PT35004,China)the Drug Innovation Major Project from the National Science and Technology Department(2018ZX09711001-003-005 and 2018ZX09711001-003-001,China)the National Key R&D Program of China(2017YFA0205400 and 2022YFC2505204,China).
文摘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 PPARa 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 PPARa 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 PPARa 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.
