Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity

doi:10.1016/j.cmet.2024.03.003

	Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity
	Tong, Lingfeng 1; Chen, Zhangbing 1; Li, Yangyang2 ; Wang, Xinxia 1; Yang, Changjie 3; Li, Yakui 1; Zhu, Yemin 1; Lu, Ying 4; Liu, Qi 5; Xu, Nannan 1; Shao, Sijia 1; Wu, Lifang 1; Zhang, Ping 1; Wu, Guangyu 6; Wu, Xiaoyu 7; Chen, Xiaosong 3; Fang, Junwei 8; Jia, Renbing 9; Xu, Tianle 10,11; Li, Bin 12; Zheng, Liang 7; Liu, Junling 1,13; Tong, Xuemei 1
	2024-05-07
发表期刊	CELL METABOLISM (IF:27.7[JCR-2023],31.2[5-Year])
ISSN	1550-4131
EISSN	1932-7420
卷号	36 期号:5
发表状态	已发表
DOI	10.1016/j.cmet.2024.03.003
摘要	Metabolic dysfunction -associated fatty liver disease (MAFLD) has a global prevalence of about 25% and no approved therapy. Using metabolomic and proteomic analyses, we identified high expression of hepatic transketolase (TKT), a metabolic enzyme of the pentose phosphate pathway, in human and mouse MAFLD. Hyperinsulinemia promoted TKT expression through the insulin receptor-CCAAT/enhancer-binding protein alpha axis. Utilizing liver -specific TKT overexpression and knockout mouse models, we demonstrated that TKT was sufficient and required for MAFLD progression. Further metabolic flux analysis revealed that Tkt deletion increased hepatic inosine levels to activate the protein kinase A-cAMP response element binding protein cascade, promote phosphatidylcholine synthesis, and improve mitochondrial function. Moreover, insulin induced hepatic TKT to limit inosine-dependent mitochondrial activity. Importantly, N-acetylgalactosamine (GalNAc)-siRNA conjugates targeting hepatic TKT showed promising therapeutic effects on mouse MAFLD. Our study uncovers how hyperinsulinemia regulates TKT-orchestrated inosine metabolism and mitochondrial function and provides a novel therapeutic strategy for MAFLD prevention and treatment.
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收录类别	SCI
语种	英语
资助项目	National Key Research and Development Program of China[
WOS研究方向	Cell Biology ; Endocrinology & Metabolism
WOS类目	Cell Biology ; Endocrinology & Metabolism
WOS记录号	WOS:001239829500001
出版者	CELL PRESS
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/387262
专题	生命科学与技术学院生命科学与技术学院_PI研究组_李扬扬组
通讯作者	Liu, Junling; Tong, Xuemei
作者单位	1.Shanghai Jiao Tong Univ, Dept Biochem & Mol Cell Biol, Shanghai Key Lab Tumor Microenvironm & Inflammat, Key Lab Cell Differentiat & Apoptosis,Chinese Min, Shanghai 200025, Peoples R China 2.Shanghai Tech Univ, Sch Life Sci & Technol, Unit Immune & Metab Regulat, Shanghai 201210, Peoples R China 3.Shanghai Jiao Tong Univ, RenJi Hosp, Sch Med, Dept Liver Surg, Shanghai 200127, Peoples R China 4.Fudan Univ, Dept Biochem & Mol Biol, Key Lab Metab & Mol Med, Minist Educ,Sch Basic Med Sci,Shanghai Med Coll, Shanghai 200032, Peoples R China 5.Gladstone UCSF Inst Genom Immunol, San Francisco, CA USA 6.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Radiol, Shanghai 200127, Peoples R China 7.Shanghai Jiao Tong Univ, Pediat Translat Med Inst, Shanghai Childrens Med Ctr, Key Lab Pediat Hematol & Oncol,Sch Med,Minist Hlt, Shanghai 200127, Peoples R China 8.Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Natl Clin Res Ctr Eye Dis, Shanghai Key Lab Ocular Fundus Dis,Dept Ophthalmo, Shanghai 200032, Peoples R China 9.Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Sch Med, Dept Ophthalmol, Shanghai 200011, Peoples R China 10.Shanghai Jiao Tong Univ, Ctr Brain Sci, Shanghai Childrens Med Ctr, Sch Med, Shanghai 200062, Peoples R China 11.Shanghai Jiao Tong Univ, Sch Med, Dept Anat & Physiol, Shanghai 200025, Peoples R China 12.Shanghai Jiao Tong Univ, Shanghai Inst Immunol, Sch Med, Dept Immunol & Microbiol, Shanghai 200025, Peoples R China 13.Shanghai Synvida Biotechnol Co Ltd, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Tong, Lingfeng,Chen, Zhangbing,Li, Yangyang,et al. Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity[J]. CELL METABOLISM,2024,36(5).
APA	Tong, Lingfeng.,Chen, Zhangbing.,Li, Yangyang.,Wang, Xinxia.,Yang, Changjie.,...&Tong, Xuemei.(2024).Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity.CELL METABOLISM,36(5).
MLA	Tong, Lingfeng,et al."Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity".CELL METABOLISM 36.5(2024).